Protein tyrosine kinase agonist antibodies

ABSTRACT

Agonist antibodies are disclosed which bind to the extracellular domain of receptor protein tyrosine kinases pTKs, and thereby cause dimerization and activation of the intracellular tyrosine kinase domain thereof. The antibodies are useful for activating their respective receptor and thereby enabling the role of the tyrosine kinase receptor in cell growth and/or differentiation to be studied. Chimeric proteins comprising the extracellular domain of the receptor pTKs and an immunoglobulin constant domain sequence are also disclosed.

This application is the U.S. National phase of PCT/US95/04228 filed Apr.4, 1995 which is a continuation-in-part of U.S. Ser. No. 08/222,616filed Apr. 4, 1994 (now U.S. Pat. No. 5,635,177) which is acontinuation-in-part of PCT/US93/00586, filed Jan. 22, 1993 (which isNational stage entry U.S. Ser. No. 08/256,769 filed Sep. 15, 1994), nowabandoned which is a continuation-in-part of U.S. Ser. No. 07/826,935filed Jan. 22, 1992 (now abandoned).

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to novel protein tyrosine kinase (pTK)genes, the proteins encoded by these genes, RNA nucleic acid sequenceswhich hybridize to the genes, antibodies specific for the encodedproteins, chimeras of the proteins and methods of use therefor.

In particular, this application relates to agonist antibodies which areable to activate the tyrosine kinase domain of the receptor pTKsdisclosed herein and pTK-immunoglobulin chimeras.

2. Description of Related Art

Transduction of signals that regulate cell growth and differentiation isregulated in part by phosphorylation of various cellular proteins.Protein tyrosine kinases are enzymes that catalyze this process.Moreover, many act as growth factor receptors. The c-kit subgroup ofreceptor tyrosine kinases catalyze the phosphorylation of exogenoussubstrates, as well as tyrosine residues within their own polypeptidechains (Ullrich et al., Cell 61:203 [1990]). Members of the c-kitsubgroup include FLT/FLK (Fetal Liver Kinase), FGF (Fibroblast GrowthFactor Receptor) and NGF (Nerve Growth Factor Receptor).

The EPH tyrosine kinase subfamily, Eph, Elk, Eck, Eek, Hek, Hek2, Sek,Ehk-1, Ehk-2, Cek-4 to -10, Tyro 1, 4, 5 and 6, appears to be thelargest subfamily of transmembrane tyrosine kinases (Hirai et al.,Science 238:1717-1720 [1987]; Letwin et al., Oncogene 3:621-678 [1988];Lhotak et al., Mol. Cell. Biol. 13:7071-7079 [1993]; Lindberg et al.,Mol. Cell. Biol. 10:6316-6324 [1990]; Bohme et al., Oncogene 8:2857-2862[1993]; and Wicks et al., Proc. Natl. Acad. Sci. USA. 89:1611-1615[1992]; Pasquale et al. Cell Regulation 2:523-534 [1991]; Sajjadi etal., New Biol. 3:769-778 [1991]; Wicks et al., Proc. Natl. Acad. Sci.USA. 89:1611-1615 [1992]; Lhotak et al., Mol. Cell. Bio. 11:2496-2502[1991]; Gilardi-Hebenstreit et al., Oncogene 7:2499-2506 [1992]; Lai etal., Neuron 6:691-704 [1991]; Sajjadi et al., Oncogene 8:1807-1813[1993]; and Maisonpierre et al., Oncogene 8:3277-3288 [1993]).

Additional pTKs and agonist antibodies thereto are needed in order tofurther study growth and differentiation of cells, for use astherapeutic agents and for diagnostic purposes. Accordingly, it is anobject of the present invention to provide novel pTK genes, the proteinsencoded thereby, antibodies specific for the encoded proteins, chimerasof the proteins and methods of use thereof.

SUMMARY OF THE INVENTION

The genes isolated as described herein are referred to, collectively, as“protein tyrosine kinase genes” or “pTK genes”. The nucleic acidsequences of some of these genes, isolated as discussed herein, showsignificant homology with previously identified protein tyrosine kinasescontaining extracellular domains, which function as growth factorreceptors (e.g., pTKs of the c-kit subgroup). Some of the pTK genes havebeen shown to be present in both megakaryocytic and lymphocytic cells.

In particular, fourteen pTK genes have been identified. Two pTK genes,referred to as SAL-S1 and SAL-D4 were identified in megakaryocyticcells. SAL-D4 is related to the CSK family of intracellular pTKs andSAL-S1 is related to the FGF receptor family of pTKs. Five pTK genes,referred to as LpTKs, were identified in lymphocytic cells and have beenshown to be present in megakaryocytes as well. One pTK gene, referred toas HpTK5, was identified in human hepatoma cells. Six pTK genes,referred to as bpTK genes, were found in human brain tissue.

The pTK genes, which are the subject of the present invention, weregenerally identified using two sets of degenerative oligonucleotideprimers: a first set which amplifies all pTK DNA segments (SEQ ID NOS:1-2), and a second set which amplifies highly conserved sequencespresent in the catalytic domain of the c-kit subgroup of pTKs (SEQ IDNOS: 3-4). The pTK genes identified in this manner are described below.

SAL-S1 is expressed in several megakaryocytic cell lines, but not inerythroid cell lines. The nucleotide sequence of part of SAL-S1 wasobtained, revealing a sequence containing 160 base pairs (SEQ ID NO: 5).This isolated DNA fragment encoded an amino acid sequence (SEQ ID NO: 6)which exhibited significant sequence homology with known proteintyrosine kinases of the FLT/FLK family. The deduced amino acid sequenceof SAL-S1 (SEQ ID NO: 33) contains 1298 residues.

SAL-D4, also expressed in megakaryocytic cells, is a DNA fragmentcontaining the nucleotide sequence of 147 base pairs. (SEQ ID NO: 7).This isolated DNA fragment encoded an amino acid sequence (SEQ ID NO: 8)which exhibited significant sequence homology with known proteintyrosine kinases of the CSK intracellular pTK family.

The LpTKs, including LpTK 2, LpTK 3, LpTK 4, LpTK 13 and LpTK 25, areexpressed in lymphocytic cells, as well as megakaryocytic cells. Thenucleotide sequence (151 base pairs) of the LpTK 3 gene was obtained(SEQ ID NO: 11). The nucleotide sequences of the LpTK 2, LPTK 4, andLpTK 13 genes contained 149 base pairs (SEQ ID NO: 9), 137 base pairs(SEQ ID NO: 13), and 211 base pairs (SEQ ID NO: 15) respectively. LpTK25 has a nucleotide sequence of 3120 b.p. (SEQ ID NO: 22). A full lengthgene sequence has been obtained for LpTK 2 (SEQ ID NO: 19) whichcontains 7607 b.p. Additional sequencing of LpTK 4 revealed a sequenceof 404 b.p. (SEQ ID NO: 21).

The HpTK5 gene, expressed in human hepatoma cells, has a nucleotidesequence of 3969 b.p. (SEQ ID NO: 23).

Nucleotide sequences of the bpTKs, including bpTK 1, bpTK 2, bpTK 3,bpTK 4, bpTK 5 and bpTK 7, are expressed in human brain tissue andencode proteins having the amino acid sequences of SEQ ID NOS: 25-29 and34 respectively.

Thus, the present invention includes DNA isolated from a humanmegakaryocytic cell line, which hybridizes to DNA encoding an amino acidsequence which is highly conserved in the catalytic domain of proteintyrosine kinases of the c-kit subgroup.

The present invention also includes the proteins encoded by the pTKgenes identified as described herein, which exhibit significant sequencehomology with members of the c-kit subgroup of pTKs as well as theproteins encoded by HpTK5 and the bpTKs. The present invention alsoincludes SAL-S1, SAL-D4, LpTK, HpTK5 and bpTK homologues or equivalents(i.e., proteins which have amino acid sequences substantially similar,but not identical, to that of SAL-S1, SAL-D4, the LpTKs, HpTK5 and thebpTKs, which exhibit tyrosine kinase activity). This invention furtherincludes peptides (SAL-S1, SAL-D4, LpTK, HpTK5 and bpTK fragments) whichretain tyrosine kinase activity, yet are less than the entire SAL-S1,SAL-D4, LpTK, HpTK5 and bpTK sequences; and uses for the SAL-S1, SAL-D4,the LpTK, HpTK and the bpTK nucleic acid sequences and SAL-S1, SAL-D4,LpTK, HpTK and bpTK equivalents.

The present invention further includes nucleic acid sequences whichhybridize with DNA or RNA encoding the proteins described herein, whichexhibit significant sequence homology with the FLT/FLK, FGF receptor orNGF receptor family of protein tyrosine kinases contained within thec-kit subgroup. Such nucleic acid sequences are useful as probes toidentify pTK genes in other vertebrates, particularly mammals. and inother cell types. They can also be used as anti-sense oligonucleotidesto inhibit protein tyrosine kinase activity, both in vitro and in vivo.

The SAL-S1, SAL-D4, LpTK, HpTK and bpTK tyrosine kinases of the presentinvention can be used as target proteins in conjunction with thedevelopment of drugs and therapeutics to modulate cell growth,differentiation and other metabolic functions. The SAL-S1, SAL-D4, LpTK,HpTK or bpTK proteins can be used as agonists or antagonists to othertyrosine kinases. The pTKs can also be instrumental in the modulation ofmegakaryocyte and/or platelet adhesion interactions.

In addition, the SAL-S1, SAL-D4, LpTK, HpTK and bpTK tyrosine kinasescan be used in screening assays to detect cellular growth and/ordifferentiation factors. Using standard laboratory techniques, theligands of the pTKs of the present invention can be identified. Inparticular, the invention provides chimeric pTK-immunoglobulin fusionproteins which are useful for isolating ligands to the pTKs disclosedherein. The chimeric proteins are also useful for diagnostic assaysdesigned to detect these ligands present endogenously, within cells, aswell as exogenously, in extra-cellular fluids. Assays, using thechimeric proteins, can also be designed as diagnostic aids to detectthese ligands in body fluids such as blood and urine.

In another aspect, the invention provides antibodies specific forSAL-S1, SAL-D4, the LpTKs, HpTK5 and the bpTKs, which are optionallyagonists for their respective pTK (where the pTK is a receptor). Theinvention also concerns a hybridoma cell line and an isolated nucleicacid encoding a monoclonal antibody as herein defined.

Also, the invention pertains to a method for activating a pTK as hereindisclosed, comprising reacting the pTK with an agonist antibody thereto.In a different aspect, the invention concerns a method for enhancingcell growth and/or differentiation comprising administering to a humanpatient in need of such treatment a physiologically effective amount ofan agonist antibody which activates a pTK as herein disclosed.

In a still further aspect, the invention concerns a method for detectinga pTK by contacting a source suspected of containing the pTK with adetectably labeled monoclonal antibody which reacts immunologically withthe pTK, and determining whether the antibody binds to the source.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A and 1B depict the nucleotide sequence of SAL-S1 (SEQ ID NO: 5)and its deduced amino acid sequence (SEQ ID NO: 6).

FIGS. 2A and 2B depict the nucleotide sequence of SAL-D4 (SEQ ID NO: 7)and its deduced amino acid sequence (SEQ ID NO: 8).

FIG. 3A depicts the nucleotide sequence of LpTK 2 (SEQ ID NO: 9) and itsdeduced amino acid sequence (SEQ ID NO: 10).

FIG. 3B depicts the nucleotide sequence of LpTK 3 (SEQ ID NO: 11) andits deduced amino acid sequence (SEQ ID NO: 12).

FIG. 3C depicts the nucleotide sequence of LpTK 4 (SEQ ID NO: 13) andits deduced amino acid sequence (SEQ ID NO: 14).

FIG. 3D depicts the nucleotide sequence of LpTK 13 (SEQ ID NO: 15) andits deduced amino acid sequence (SEQ ID NO: 16).

FIGS. 4A-4I depict the nucleotide sequence (SEQ ID NO: 17) of SAL-S1 andits deduced amino acid sequence (SEQ ID NO: 18).

FIGS. 5A-5K depict the full length nucleotide sequence (SEQ ID NO: 19)of LpTK2 and its deduced amino acid sequence (SEQ ID NO: 20).

FIG. 6 depicts the partial nucleotide sequence (SEQ ID NO: 21) forLpTK4.

FIGS. 7A-7C depict the full length nucleotide sequence (SEQ ID NO: 22)for LpTK25.

FIGS. 8A-8I depict the full length nucleotide sequence (SEQ ID NO: 23)and the deduced amino acid sequence of HpTK5 (SEQ ID NO: 24).

FIG. 9 depicts the amino acid sequence (SEQ ID NO: 25) of bpTK1.

FIG. 10 depicts the amino acid sequence (SEQ ID NO: 26) of bpTK2.

FIG. 11 depicts the amino acid sequence (SEQ ID NO: 27) of bpTK3.

FIG. 12 depicts the amino acid sequence (SEQ ID NO: 28) of bpTK4.

FIG. 13 depicts the amino acid sequence (SEQ ID NO: 29) of bpTK5.

FIG. 14 depicts the amino acid sequence (SEQ ID NO: 30) of bpTK7.

FIGS. 15A-15F depict the full-length nucleotide sequence of SAL-S1 (SEQID NO: 31) to complement (SEQ ID NO 32) and its deduced amino acidsequence (SEQ ID NO: 33).

FIGS. 16A-16H depict the full-length nucleotide sequence of bpTK7 (SEQID NO: 34) to complement (SEQ ID NO: 35) and its deduced amino acidsequence (SEQ ID NO: 36).

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Novel protein tyrosine kinase genes have been identified, their nucleicacid sequences determined, and the amino acid sequences of the encodedproteins deduced. The genes isolated as described herein are referredto, collectively, as “protein tyrosine kinase genes” or “pTK genes”.

To facilitate the isolation and identification of these novel pTKs, twosets of DNA probes were used, as described in Example 1. The first setgenerally consisted of two degenerative oligonucleotide sequences, pTK 1(SEQ ID NO: 1) and pTK 2 (SEQ ID NO: 2) (Matthews, Cell 65:1143 [1991];and Wilks, Proc. Natl. Acad. Sci. USA 86:1603 [1989]). These sequenceswere used as primers in a polymerase chain reaction to amplify tyrosinekinase DNA segments (Mullis, et al., Cold Spring Harbor Symp. Advan.Biol. 51:263 [1986]).

The second set generally consisted of two oligonucleotide sequences, pTK3 (SEQ ID NO: 3) and pTKKW (SEQ ID NO: 4) designed to amplify thenucleic acid sequence which encodes the highly conserved regions of thecatalytic domains of the c-kit family of protein tyrosine kinases. Thesesequences were used as primers in the polymerase chain reaction (PCR) ina second round of DNA amplification. Using this two-step amplificationprocedure, DNA fragments which hybridized to these pTK primers wereidentified, isolated and subsequently sequenced.

In particular, fourteen pTK genes have been identified. Two pTK genes,referred to as SAL-S1 and SAL-D4, were identified in severalmegakaryocytic cell lines, including CMK 11-5, DAMI, UT-7 and UT-7 grownin erythropoietin, but not in the erythroid cell lines HEL, PMAstimulated HEL cells, or K562. Five pTK genes, referred to as LpTKs,were identified in lymphocytic, as well as in megakaryocytic cells. OnepTK gene, referred to as HpTK5, was identified in human hepatoma cells,and six genes, referred to as bpTKs, were identified in human braintissue.

SAL-S1 (SEQ ID NOS: 6, 18 and 33) encoded by the nucleic acid sequenceof SEQ ID NOS: 5, 17 and 31 exhibits significant homology with theFLT/FLK family of pTKs. SAL-S1 has a signal peptide (i.e., amino acidresidues 1 to 24 of FIG. 15); extracellular domain (i.e., amino acidresidues 25 to 775 of FIG. 15); transmembrane domain (i.e., amino acidresidues 776 to 800 of FIG. 15) and a cytoplasmic tyrosine kinase domain(i.e., amino acid residues 801 to 1298 of FIG. 15). SAL-D4 (SEQ ID NO:8) encoded by SEQ ID NO: 7 is related to the CSK family of intracellularpTKs. The LpTKs, LpTK 2 (SEQ ID NOS: 10 and 20) encoded by SEQ ID NOS: 9and 19; LpTK 3 (SEQ ID NO: 12) encoded by SEQ ID NO: 11; LpTK4 (SEQ IDNO: 14) encoded by SEQ ID NOS: 13 and 21; LpTK13 (SEQ ID NO: 16) encodedby SEQ ID NO: 15; and LpTK25 encoded by SEQ ID NO: 22, also exhibitsequence homology with known protein tyrosine kinases.

HpTK5 (SEQ ID NO: 24) encoded by SEQ ID NO: 23 and the bpTKs 1, 2, 3, 4,5 and 7 (SEQ ID NOS: 25-29 and 36 respectively), similarly exhibitsequence homology with known protein tyrosine kinases. BpTK7 encodes areceptor pTK with a signal peptide (i.e., amino acid residues 1-19 ofFIG. 16); extracellular domain (i.e., amino acid residues 20-547 of FIG.16); and transmembrane domain (i.e., amino acid residues 548-570 of FIG.16). The remaining sequence comprises the intracellular tyrosine kinasedomain.

Thus, as described above, DNA molecules which hybridize with DNAencoding amino acid sequences present in the catalytic domain of aprotein tyrosine kinase of the c-kit subgroup of protein kinases havebeen isolated and sequenced. These isolated DNA sequences, collectivelyreferred to as “pTK genes”, (and their deduced amino acid sequences)have been shown to exhibit significant sequence homology with knownmembers of pTK families.

Once isolated, these DNA fragments can be amplified using known standardtechniques such as PCR. These amplified fragments can then be clonedinto appropriate cloning vectors and their DNA sequences determined.

These DNA sequences can be excised from the cloning vectors, labeledwith a radiolabeled nucleotide such as ³²P and used to screenappropriate cDNA libraries to obtain the full-length cDNA clone.

The pTK genes as described above have been isolated from the source inwhich they occur naturally, e.g., megakaryocytic and lymphocytic cells.The present invention is intended to include pTK genes produced usinggenetic engineering techniques, such as recombinant technology, as wellas pTK genes that are synthesized chemically.

The deduced amino acid sequences of the pTK genes include amino acidsequences which encode peptides exhibiting significant homology with thecatalytic domain of protein tyrosine kinases of the c-kit subgroup oftyrosine kinases. These proteins, encoded by the pTK genes, can includesequences in which functionally equivalent amino acid residues aresubstituted for residues within the sequence, resulting in a silentchange, that is a change not detected phenotypically. For example, oneor more amino acid residues within the sequence can be substituted byanother amino acid of a similar polarity which acts as a functionalequivalent, resulting in a silent substitution.

In addition, the protein structure can be modified by deletions,additions, inversion, insertions or substitutions of one or more aminoacid residues in the sequence which do not substantially detract fromthe desired functional tyrosine kinase properties of the peptide.

Modified pTKs of the present invention, with tyrosine kinase activity,can be made using recombinant DNA techniques, such as excising it from avector containing a cDNA encoding such a protein, or by synthesizing DNAencoding the desired protein mechanically and/or chemically using knowntechniques.

An alternate approach to producing the pTKs of the present invention isto use peptide synthesis to make a peptide or polypeptide having theamino acid sequence of such a protein, depending on the length of thepTK desired. The peptides or modified equivalents thereof, can besynthesized directly by standard solid or liquid phase chemistries forpeptide synthesis.

Preferably, the pTKs of the present invention will be produced byinserting DNA encoding the proteins into an appropriate vector/hostsystem where it will be expressed. The DNA sequences can be obtainedfrom sources in which they occur naturally, can be chemicallysynthesized or can be produced using standard recombinant technology.

This invention also pertains to an expression vector comprising a pTKgene of the present invention, encoding for a protein which exhibitsreceptor tyrosine kinase activity.

The pTK genes of the present invention can be used for a number ofdiagnostic and therapeutic purposes. For example, the nucleic acidsequences of the pTK genes can be used as probes to identify otherprotein tyrosine kinases present in other cell types, includingeukaryotic and prokaryotic cell types.

The nucleic acid sequences can also be used to design drugs thatdirectly inhibit the kinase activity of protein tyrosine kinases, or todesign peptides that bind to the catalytic domain of tyrosine kinases,thus inhibiting their activity. These sequences can also be used todesign anti-sense nucleotides that can also inhibit, or destroy,tyrosine kinase activity. Such inhibition of tyrosine kinase activitywould be desirable in pathological states where decreased cellularproliferation would be beneficial, such as leukemias or othermalignancies.

The nucleic acid sequences can also be used to design drugs, peptides oranti-sense nucleotides as above, but with enhancing, rather thaninhibitory effects, on tyrosine kinases. Such enhanced tyrosine kinaseactivity would result in increasing the phosphorylation of substrates(exogenous, as well as endogenous tyrosine residues). Enhanced effectswould be desirable in states where increased cellular proliferationwould be beneficial, such as anemias, bleeding disorders and duringsurgical procedures.

The pTK genes of the present invention can also be used to obtainsoluble fragments of receptor tyrosine kinases, capable of binding theirrespective ligands. pTK genes encoding soluble tyrosine kinase fragmentscan be produced using recombinant DNA techniques or synthetically. Ineither case, the DNA obtained encodes a soluble pTK fragment which lacksa substantial portion of the hydrophobic transmembrane region to permitsolubilization of the fragment.

These soluble pTK protein fragments can be introduced exogenously to actas competitors with the endogenous, membrane bound pTK for theirrespective ligands, thus inhibiting tyrosine kinase activity.Alternately, a modified soluble pTK protein fragment can be introducedwhich binds the ligand but does not activate kinase activity.

These soluble pTK protein fragments can also be used in binding assaysto detect ligands such as growth and differentiation factors. Once theseligands are identified, they may be altered or modified to inhibit orenhance kinase activity. For example, the ligands may be modified orattached to substances that are toxic to the cell, such a ricin, thusdestroying the target cell. The substance may be a super-activatingsubstance which, after binding to the pTK, may substantially increasethe kinase activity, or activate other growth factors.

pTK genes of the present invention would also be useful to developdiagnostic tools for in vitro screening assays for ligands such asgrowth factors or differentiation factors that inhibit or enhance kinaseactivity. The proteins encoded by the pTK genes can also be used in suchassays, or as immunogens to produce monoclonal or polyclonal antibodiesto be used in such assays.

In one embodiment of the invention, a chimera comprising a fusion of theextracellular domain of the pTK (where the pTK is a receptor) and animmunoglobulin constant domain can be constructed which can be used toassay for ligands for the receptor and can be used for the production ofantibodies against the extracellular domain of the receptor.

The expression “extracellular domain” or “ECD” when used herein refersto any polypeptide sequence that shares a ligand binding function of theextracellular domain of the naturally occurring receptor pTKs disclosedherein. Ligand binding function of the extracellular domain refers tothe ability of the polypeptide to bind at least one pTK ligand.Accordingly, it is not necessary to include the entire extracellulardomain since smaller segments are commonly found to be adequate forligand binding. The truncated extracellular domain is generally soluble.The term ECD encompasses polypeptide sequences in which the hydrophobictransmembrane sequence (and, optionally, 1-20 amino acids C-terminaland/or N-terminal to the transmembrane domain) of the mature pTK hasbeen deleted. Thus, the soluble extracellular domain-containingpolypeptide can comprise the extracellular domain and the cytoplasmicdomain of the pTK. Alternatively, in the preferred embodiment, thepolypeptide comprises only the extracellular domain of the pTK. Theextracellular and transmembrane domains of the pTK can be readilydetermined by the skilled practitioner by aligning the pTK of interestwith known pTK amino acid sequences for which these domains have beendelineated. Alternatively, the hydrophobic transmembrane domain can bereadily delineated based on a hydrophobicity plot of the sequence. Theextracellular domain is N-terminal to the transmembrane domain.

The term “immunoglobulin” generally refers to polypeptides comprising alight or heavy chain usually both disulfide bonded in the native “Y”configuration, although other linkage between them, including tetramersor aggregates thereof, is within the scope hereof.

Immunoglobulins (Ig) and certain variants thereof are known and manyhave been prepared in recombinant cell culture. For example, see U.S.Pat. No. 4,745,055; EP 256,654; Faulkner et al., Nature 298:286 [1982];EP 120,694; EP 125,023; Morrison, J. Immun. 123:793 [1979]; Köhler etal., Proc. Nat'l. Acad. Sci. USA 77:2197 [1980]; Raso et al., CancerRes. 41:2073 [1981]; Morrison et al., Ann. Rev. Immunol. 2:239 [1984];Morrison, Science 229:1202 [1985]; Morrison et al., Proc. Nat'l. Acad.Sci. USA 81:6851 [1984]; EP 255,694; EP 266,663; and WO 88/03559.Reassorted immunoglobulin chains also are known. See for example U.S.Pat. No. 4,444,878; WO 88/03565; and EP 68,763 and references citedtherein. The immunoglobulin moiety in the chimera of the presentinvention may be obtained from IgG₁, IgG₂, IgG₃, or IgG₄ subtypes, IgA,IgE, IgD or IgM, but preferably IgG₁ or IgG₃. Most preferably, theimmunoglobulin moiety is the Fc portion of IgG-γ.

The terms “chimera comprising a fusion of an extracellular domain of apTK with an immunoglobulin constant domain sequence” or“pTK-immunoglobulin chimera” refer to a polypeptide comprising anextracellular domain coding amino acid sequence of a pTK conjugated toan immunoglobulin constant domain sequence. This definition includeschimeras in monomeric, homo- or heteromultimeric, and particularly homo-or heterodimeric, or -tetrameric forms.

A preferred embodiment is the fusion of the C-terminus of theextracellular domain of a pTK, to the N-terminus of the C-terminalportion of an antibody (in particular the Fc domain), containing theeffector functions of immunoglobulin G₁. In a preferred embodiment, theentire heavy chain constant region is fused to the extracellular domain.In another preferred embodiment, a sequence beginning in the hingeregion just upstream of the papain cleavage site (which defines IgG Fcchemically; residue 216, taking the first residue of heavy chainconstant region to be 114 (Kabat et al., Sequences of ImmunologicalInterest, National Institutes of Health, Bethesda, Md., [1987]), oranalogous sites of other immunoglobulins) is fused to the ECD of thepTK.

In a particularly preferred embodiment, the pTK extracellular domain isfused to the hinge region and C_(H)2 and C_(H)3 or C_(H)1, hinge, C_(H)2and C_(H)3 domains of an IgG₁, IgG₂ or IgG3 heavy chain. The precisesite at which the fusion is made is not critical, and the optimal sitecan be determined by routine experimentation. A principal advantage ofthe chimeras is that they are secreted into the culture medium ofrecombinant hosts, although the degree of secretion might be differentfor various expression systems.

In general, the chimeras of the present invention are constructed in afashion similar to chimeric antibodies in which a variable domain froman antibody of one species is substituted for the variable domain ofanother species. See, for example, EP 0 125 023; EP 173,494; Munro,Nature 312: [Dec. 13, 1984]; Neuberger et al., Nature 312: [Dec. 13,1984]; Sharon et al., Nature 309: [May 24, 1984]; Morrison et al., Proc.Nat'l. Acad. Sci. USA 81:6851-6855 [1984]; Morrison et al. Science229:1202-1207 [1985]; Boulianne et al., Nature 312:643-646 [Dec. 13,1984]; Capon et al., Nature 337, 525-531 [1989]; Traunecker et al.,Nature 339, 68-70 [1989].

To prepare the pTK-Ig chimeric polypeptides, the DNA including a regionencoding the desired pTK sequence is cleaved by a restriction enzyme ator proximal to the 3′ end of the DNA encoding the immunoglobulin-likedomain(s) and at a point at or near the DNA encoding the N-terminal endof the mature pTK (where use of a different leader is contemplated) orat or proximal to the N-terminal coding region for the pTK (where thenative signal is employed). This DNA fragment then is readily insertedproximal to DNA encoding an immunoglobulin light or heavy chain constantregion and, if necessary, the resulting construct tailored by deletionalmutagenesis. Preferably, the Ig is a human immunoglobulin when thevariant is intended for in vivo therapy for humans. DNA encodingimmunoglobulin light or heavy chain constant regions is known or readilyavailable from cDNA libraries or is synthesized. See for example, Adamset al., Biochemistry 19:2711-2719 [1980]; Gough et al., Biochemistry19:2702-2710 [1980]; Dolby et al., P.N.A.S. USA, 77:6027-6031 [1980];Rice et al., P.N.A.S. USA 79:7862-7865 [1982]; Falkner et al., Nature298:286-288 [1982]; and Morrison et al., Ann. Rev. Immunol. 2:239-256[1984].

The chimeric proteins disclosed herein are useful as diagnostics forisolating or screening ligands for the pTK of interest using thetechniques of Lyman et al., Cell 75:1157-1167 [1993], for example. Also,the chimeric proteins are useful for diagnostic purposes for studyingthe interaction of various ligands with the extracellular domain of thevarious pTKs (see, e.g., Bennett et al., J. Biol. Chem.266(34):23060-23067 [1991]). The chimeric proteins are further usefulfor the production of antibodies against the extracellular domain of thepTK (see Examples 3 and 5 herein). The chimeric proteins also have anadditional therapeutic utility insofar as they provide a soluble form ofthe extracellular domain of the pTK which generally has an enhancedplasma half life (compared to the extracellular domain only) andtherefore can be formulated in a pharmaceutically acceptable carrier andadministered to a patient. The chimeric proteins are believed to finduse as therapeutic agents for removal of excess systemic ortissue-localized pTK ligand which has been administered to a patient.Removal of excess ligand is particularly desirably where the ligand maybe toxic to the patient. The chimeric protein acts to bind the ligand incompetition with the endogenous pTK in the patient. Similarly, it iscontemplated that the chimeric protein can be administered to a patientsimultaneously, or subsequent to, administration of the ligand in theform of a sustained release composition. The chimeric protein acts as asoluble binding protein for the ligand, thereby extending the half-lifeof the ligand.

The term “antibody” is used herein in the broadest sense andspecifically covers polyclonal antibodies, monoclonal antibodies,immunoglobulin chains or fragments thereof, which react immunologicallywith a pTK.

In the preferred embodiment of the invention, the antibodies aremonoclonal antibodies produced using techniques which are well known inthe art. For example, the hybridoma technique described originally byKohler and Milstein, Eur. J. Immunol., 6:511 [1976], and also describedby Hammerling et al., In: Monoclonal Antibodies and T-Cell Hybridomas,Elsevier, N.Y., pp. 563-681 [1981] can be used. The techniques of Coteet al. and Boerner et al. are also available for the preparation ofhuman monoclonal antibodies [Cote et al., Monoclonal Antibodies andCancer Therapy, Alan R. Liss, p. 77 [1985] and Boerner et al., J.Immunol., 147(1):86-95 [1991]).

The term “monoclonal antibody” as used herein refers to an antibody (ashereinabove defined) obtained from a population of substantiallyhomogeneous antibodies, i.e., the individual antibodies comprising thepopulation are identical except for possible naturally occurringmutations that may be present in minor amounts. Monoclonal antibodiesare highly specific, being directed against a single antigenic site.Furthermore, in contrast to conventional (polyclonal) antibodypreparations which typically include different antibodies directedagainst different determinants (epitopes), each monoclonal antibody isdirected against a single determinant on the antigen. In addition totheir specificity, the monoclonal antibodies are advantageous in thatthey can be synthesized by a hybridoma culture, uncontaminated by otherimmunoglobulins.

“Humanized” forms of non-human (e.g., murine) antibodies areimmunoglobulins, immunoglobulin chains or fragments thereof (such as Fv,Fab, Fab′, F(ab′)₂ or other antigen-binding subsequences of antibodies)which contain minimal amino acid residues derived from a non-humanimmunoglobulin. For the most part, humanized antibodies are humanimmunoglobulins (recipient antibody) in which residues from acomplementary determining region (CDR) of the recipient are replaced byresidues from a CDR of a non-human species (donor antibody) such asmouse, rat or rabbit having the desired specificity, affinity andcapacity. In some instances, Fv framework region (FR) residues of thehuman immunoglobulin are replaced by corresponding non-human FRresidues. Furthermore, a humanized antibody may comprise residues whichare found neither in the recipient antibody nor in the imported CDR orframework sequences. These modifications are made to further refine andoptimize antibody performance.

The monoclonal antibodies herein include hybrid (chimeric) andrecombinant antibodies produced by splicing a variable (includinghypervariable) domain of an anti-pTK antibody with a constant domain(e.g., “humanized” antibodies), only one of which is directed against apTK, or a light chain with a heavy chain, or a chain from one specieswith a chain from another species, or fusions with heterologousproteins, regardless of species of origin or immunoglobulin class orsubclass designation, so long as they are able to bind to the pTK ofinterest [See, e.g., Cabilly, et al., U.S. Pat. No. 4,816,567; and Mage& Lamoyi, in Monoclonal Antibody Production Techniques and Applications,pp. 79-97 (Marcel Dekker, Inc., New York [1987]).

For “chimeric” and “humanized” antibodies see, for example, U.S. Pat.No. 4,816,567; WO 91/09968; EP 452,508; and WO 91/16927.

Thus, the modifier “monoclonal” indicates the character of the antibodyas being obtained from a substantially homogeneous population ofantibodies, and is not to be construed as requiring production of theantibody by any particular method.

In the most preferred embodiment of the invention, the antibodies areagonist antibodies. By “agonist antibody” is meant an antibody which isable to bind to, and activate, a particular pTK. For example, theagonist may bind to the extracellular domain of the pTK and therebycause dimerization of the pTK, resulting in transphosphorylation andactivation of the intracellular catalytic kinase domain. Consequently,this may result in stimulation of growth and/or differentiation of cellsexpressing the receptor in vitro and/or in vivo. The agonist antibodiesherein are preferably against epitopes within the extracellular domainof the pTK, and preferably have the same biological characteristics asthe monoclonal antibody produced by the hybridoma cell line depositedunder American Type Culture Collection Accession No. ATCC HB 11,583. By“biological characteristics” is meant the in vitro and/or in vivoactivities of the monoclonal antibody, e.g., ability to activate thekinase domain of a particular pTK, ability to stimulate cell growthand/or differentiation of cells expressing the pTK, and bindingcharacteristics of the antibody, etc. Accordingly, the antibodypreferably binds to substantially the same epitope as the anti-HpTK5monoclonal antibody specifically disclosed herein. Most preferably, theantibody will also have substantially the same or greater antigenbinding affinity of the anti-HpTK5 monoclonal antibody disclosed herein.To determine whether a monoclonal antibody has the same specificity asthe anti-HpTK5 antibody specifically disclosed (i.e., the antibodyhaving the ATCC deposit No. HB 11,583), one can, for example, use acompetitive ELISA binding assay.

DNA encoding the monoclonal antibodies useful in the method of theinvention is readily isolated and sequenced using conventionalprocedures (e.g., by using oligonucleotide probes that are capable ofbinding specifically to genes encoding the heavy and light chains ofmurine antibodies). The hybridoma cells of the invention serve as apreferred source of such DNA. Once isolated, the DNA may be placed intoexpression vectors, which are then transfected into host cells such asE. coli cells, simian COS cells, Chinese Hamster Ovary (CHO) cells, ormyeloma cells that do not otherwise produce immunoglobulin protein, toobtain the synthesis of monoclonal antibodies in the recombinant hostcells.

The agonist antibodies disclosed herein are useful for in vitrodiagnostic assays for activating the pTK receptor of interest. This isuseful in order to study the role of the receptor in cell growth and/ordifferentiation.

The pTK agonist antibodies have a further therapeutic utility in amethod for enhancing cell growth and/or differentiation comprisingadministering to a human patient in need of such treatment aphysiologically effective amount of an exogenous pTK agonist antibody.Agonist antibodies to the SAL-S1 pTK may find utility in treatingbleeding disorders and anemias, since this pTK was found to be expressedin megakaryocytic cells. The bpTK agonist antibodies may similarly beused to enhance differentiation and/or proliferation of brain cells inneurodegenerative diseases (such as Alzheimers disease) based on theexpression of these receptors in brain tissue. Finally, HpTK5 agonistantibodies may be used to enhance proliferation of primitivehematopoietic cells in patients having undergone chemo- or radiationtherapy or bone marrow transplantation.

An “exogenous” therapeutic compound is defined herein to mean atherapeutic compound that is foreign to the mammalian patient, orhomologous to a compound found in the mammalian patient but producedoutside the mammalian patient.

The antibodies of the present invention are also suitable for detectinga pTK by contacting a source suspected to contain the pTK with adetectably labeled monoclonal antibody, and determining whether theantibody binds to the source. There are many different labels andmethods of labeling known in the art. Suitable labels include, forexample, enzymes, radioisotopes, fluorescent compounds, chemi- andbioluminescent compounds, paramagnetic isotopes. The pTK may be presentin biological samples, such as biological fluids or tissues. Foranalytical or diagnostic purposes, the antibodies of the presentinvention are administered in an amount sufficient to enable thedetection of a site on a pTK for which the monoclonal antibody isspecific. The concentration of the detectably labeled monoclonalantibody should be sufficient to give a detectable signal abovebackground, when bound to a pTK epitope.

The pTK agonist antibodies disclosed herein may be administered to amammal, preferably a human, in a pharmaceutically acceptable dosageform, including those that may be administered to a human intravenouslyas a bolus or by continuous infusion over a period of time, byintramuscular, subcutaneous, intra-articular, intrasynovial,intrathecal, oral, topical, or inhalation routes.

Such dosage forms encompass pharmaceutically acceptable carriers thatare inherently nontoxic and nontherapeutic. Examples of such carriersinclude ion exchangers, alumina, aluminum stearate, lecithin, serumproteins, such as human serum albumin, buffer substances such asphosphates, glycine, sorbic acid, potassium sorbate, partial glyceridemixtures of saturated vegetable fatty acids, water, salts, orelectrolytes such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, and polyethylene glycol. Carriers for topical or gel-basedforms of antibody include polysaccharides such as sodiumcarboxymethylcellulose or methylcellulose, polyvinylpyrrolidone,polyacrylates, polyoxyethylene-polyoxypropylene-block polymers,polyethylene glycol, and wood wax alcohols. For all administrations,conventional depot forms are suitably used. Such forms include, forexample, microcapsules, nano-capsules, liposomes, plasters, inhalationforms, nose sprays, and sublingual tablets. The antibody will typicallybe formulated in such vehicles at a concentration of about 0.1 mg/ml to100 mg/ml.

Pharmaceutical compositions may be prepared and formulated in dosageforms by methods known in the art; for example, see Remington'sPharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 15thEdition 1975.

An effective amount of the pTK agonist antibody to be employedtherapeutically will depend, for example, upon the therapeuticobjectives, the route of administration, and the condition of thepatient. Accordingly, it will be necessary for the therapist to titerthe dosage and modify the route of administration as required to obtainthe optimal therapeutic effect. A typical daily dosage might range fromabout 1 μg/kg to up to 1000 mg/kg or more, depending on the factorsmentioned above. Typically, the clinician will administer the moleculeuntil a dosage is reached that achieves the desired effect. The progressof this therapy is easily monitored by conventional assays.

Depending on the type and severity of the disease, from about 0.001mg/kg to about 1000 mg/kg, more preferably about 0.01 mg to 100 mg/kg,more preferably about 0.010 to 20 mg/kg of the agonist antibody might bean initial candidate dosage for administration to the patient, whether,for example, by one or more separate administrations, or by continuousinfusion. For repeated administrations over several days or longer,depending on the condition, the treatment is repeated until a desiredsuppression of disease symptoms occurs or the desired improvement in thepatient's condition is achieved. However, other dosage regimens may alsobe useful.

The present invention will now be illustrated by the following Examples,which are not intended to be limiting in any way. The disclosures of allliterature references cited in the specification are expresslyincorporated herein by reference.

EXAMPLE 1 Identification and Isolation of pTK Genes

To facilitate the isolation and identification of these novel pTK genes,two sets of DNA probes were generally used (see Table 1).

The first set consisted of two degenerate oligonucleotide sequences, pTK1 (SEQ ID NO: 1) and pTK 2 (SEQ ID NO: 2). These sequences were used aspolymerase chain reaction (PCR) primers, using standard PCR techniques,to amplify tyrosine kinase DNA segments.

The second set consisted of two oligonucleotide sequences, pTK 3 (SEQ IDNO: 3) and pTKKW (SEQ ID NO: 4) selected from the highly conservedregions of the catalytic domains of the c-kit subgroup of proteintyrosine kinases. These sequences were also used as polymerase chainreaction primers in a second round of DNA amplification. Using thistwo-step amplification procedure, DNA fragments which hybridized tothese pTK primers were identified, isolated and subsequently sequencedusing known laboratory techniques.

TABLE 1 Probe name Sequence First Round of Amplification pTK15′-CGGATCCACAGNGACCT-3′ (SEQ ID NO: 1) PTK25′-GGAATTCCAAAGGACCAGACGTC-3′ (SEQ ID NO: 2) Second Round ofAmplification pTK3  (kit family specific) 5′-CGGATCCATCCACAGAGATGT-3′(SEQ ID NO: 3) pTKKW (kit family specific)5′-GGAATTCCTTCAGGAGCCATCCACTT-3′ (SEQ ID NO: 4)

EXAMPLE 2 Isolation and Characterization of HpTK5

A. DNA Amplification and Cloning of HpTK5

Light density human bone marrow mononuclear cells, obtained from normalvolunteers using Deaconess Hospital Institutional Review Board approvedprotocols and with voluntary written informed consent, were separated byanti-CD34 antibody (AMAC, Westbrook, Me.) and immunomagnetic beads(Dynal, Oslo, Norway) . Flow cytometric analysis using FITC-conjugatedanti-CD34 antibody (AMAC) confirmed ˜95% CD34 positivity of isolatedcells. The hepatoma cell line, Hep3B, was cultured in alpha medium(Gibco, Grand Island, N.Y.) supplemented with penicillin (100 U/mL),streptomycin (100 μg/mL) and 10% fetal bovine serum (Gibco) at 37° C. ina 5% CO₂ incubator. Total RNA extracted from CD34+ bone marrowmononuclear or Hep3B cells was reverse transcribed with random primersand the Moloney murine leukemia virus reverse transcriptase (RT)following the conditions of the manufacturer (Gibco-BRL) in a 20 μlreaction. PCR was performed on the RT reaction product in a 100 μlreaction containing 50 mM KCl, 10 mM Tris-HCl (pH 8.4), 1.5 mM MgCl, 20μg/ml gelatin, 0.2 mM dNTPs, 2.5 units Taq polymerase(Perkin-Elmer/Cetus) and 50 pmol each of pTK-specific degenerate primers[pTK1 5′TCGGATCCACA/CGNGAC/TC/TTGGC 3′ (SEQ ID NO. 37), pTK1B5′TCGGATCCAC/TC/AGNGAC/TC/TTNGCNGC 3′ (SEQ ID NO. 38), pTK25′CTCGAATTCCA/GA/TAA/GC/GT/ACCAG/CACA/GTC 3′ (SEQ ID NO. 39), pTK2B5′CTCGAATTCCA/GA/TAT/CC/GT/ACCAT/AACA/GTC 3′ (SEQ ID NO. 40)] derivedfrom consensus regions among known pTKs as previously reported by others(Hanks et al., Science, 241:42-52 [1988]; Wilks, Proc. Nat. Acad. Sci.,USA 86:1603-1607 [1989]; and Matthews et al., Cell 65:1143-1152 [1991]).The PCR cycle was 1.5 min at 95° C., 2 min at 37° C. and 3 min at 63° C.repeated 35 times. The reaction product was electrophoreticallyseparated on a 2% low-melting agarose gel, purified on an Elutip-Dcolumn (Schleicher & Schuell) digested with EcoR1 and BamH1, andsubcloned into pUC19.

Recombinants were sequenced by the Sanger dideoxy method and evaluatedby the FASTA nucleic acid sequence analysis program. One clone termedHpTK5 (214 bp) was radiolabelled by random priming and used to screen anoligo dT-primed lambda gt10 Hep3B cDNA library. DNA was isolated from 17positive phage plaques and inserts were subcloned into the EcoR1 site ofpBluescript (Stratagene La Jolla, Calif.). The largest insert, a 3969 bpcDNA, was sonicated to an average size of 800-2000 bp and cloned intothe Smal site of M13. Overlapping clones were sequenced using the TaqDye Primer Cycle Method (CABI) on the Catalyst 800 Molecular Biology LabStation (ABI). Sequencing reactions were then analyzed on the ABI 373AAutomated DNA Sequenator.

A single full-length 3969 bp cDNA was isolated and sequenced. (FIGS.8A-8F). The full length clone, named hepatoma transmembrane kinase (HTK)or HpTK5, included an open reading frame extending from nucleotide 90 to3050 predicted to encode a 987 amino acid protein of 108,270 Dalton. Theputative initiation codon is preceded by an in-frame stop codonbeginning at base 78. Preceding the open reading frame is a 5′untranslated region which is GC-rich as is characteristic for manygrowth factors or growth factor receptors (Kozak, J. Cell Biol.115:887-903 [1991]).

The predicted protein sequence includes a transmembrane region (aa538-563) which divides HpTK5 into extracellular (ECD) and intracellulardomains (ICD). The ECD of 538 amino acids includes a signal peptide of15 amino acids and a cysteine-rich box containing 20 Cys residues. Inaddition, there are two fibronectin type III repeats spanning aa 321 to425 and 435 to 526. Asn at positions 208, 340 and 431 are possible sitesfor N-glycosylation.

The putative intracellular domain (ICD) contains a kinase consensusregion from position 613 through 881. This kinase region includes aputative ATP-binding consensus (Gly-X-Gly-X-X-Gly) in subdomain I atpositions 622-627. A Lys at position 647 (subdomain II) corresponds toan invariant Lys among tyrosine kinases thought to be critical for thephosphotransfer reaction. Signature regions indicative of substratespecificity suggest that HpTK5 is a tyrosine rather than aserine/threonine kinase. These include the sequence at positions 740-745in subdomain VI and the sequence at positions 783-790 in subdomain VIII.Tyrosine residues at positions 601, 619 and 741 are possible substratesfor tyrosine kinase activity.

The predicted amino acid sequence of HpTK5 most closely resembles thatof the subfamily originally defined by EPH. The pattern of expression ofthe EPH subfamily is suggestive of a role in differentiation anddevelopment. In particular, the emergence of neural elements correspondswith the expression of certain EPH-related genes. The EPH familyreceptors, Hek2 and Elk, are the most closely related pTKs to HpTK5.They share 79.3 and 76.5% identity within the ICD respectively and 45and 42% identity within the ECD respectively.

B. Chromosome Mapping of HpTK5

Somatic cell hybrid DNAs from a panel of 25 human-hamster cell lines(Bios, New Haven, Conn.) were used for chromosome localization by PCR.Two sets of primers from the 3′ untranslated region of HpTK5 werechosen. PCR was performed with 250 ng DNA and 50 pmol each of the 5′ and3′ primers, 50 mM KCl, 1.5 mM MgCl₂, 20 μg/ml gelatin, 0.2 mM dNTPs and2.5 units Taq polymerase in a final volume of 100 μl. Cycles of 94° C.for 30 sec, 60° C. for 30 sec and 72° C. for 30 sec were repeated 30times. A portion of each sample (15 μl) was electrophoresed through a1.5% agarose gel, transferred to a nylon membrane and hybridized to a³²P-labelled full length HpTK5 cDNA probe prior to 5 hourautoradiography. Positives were scored and compared to a matrix summaryof human chromosomal material present in each of the somatic cell hybridDNAs.

The 3′-untranslated region characteristically contains few, if any,intervening sequences and has a high degree of diversity among membersof gene families making it preferred in this type of analysis. Both setsof primers gave results that were consistent with human chromosome 7only. Human chromosome 7 also includes the genes for the EGF receptor,hepatocyte growth factor (HGF) receptor, HGF, platelet-derived growthfactor (PDGF) and interleukin-6. Karyotypic abnormalities involving thischromosome are common among human leukemias, particularly in aggressivemyeloid leukemias that occur following radiation, alkylating agentchemotherapy or a pre-existing myelodysplastic condition (Baer et al.,Curr. Opin. Oncol. 4:24-32 [1992]).

C. Northern Blotting of HpTK5

Poly-A selected RNA was electrophoresed through a 1.2% agarose, 2.2Mformaldehyde gel and transferred to a nylon filter. Prepared orcommercially obtained filters were hybridized in 50% formamide at 42° C.to ³²-P labeled HpTK5, glyceraldehyde-3-phosphate dehydrogenase (GAPDH)or actin cDNA inserts and washed under stringent conditions (final wash:0.1×SSC, 0.2% SDS at 65° C.). SSC is 0.15 M NaCl/0.015M Na₃citrate, pH7.6. Northern blots of human fetal or adult tissue RNA were obtainedfrom Clontech (Palo Alto, Calif.) and contained 2 μg/lane of poly Aselected RNA.

Northern blot analysis of human fetal tissues revealed a singletranscript of ˜4 Kb in heart, lung, liver and kidney, with a lessersignal detectable in brain. In adult human tissue, no signal wasdetectable in brain, while placenta had a particularly intense signalfollowed by kidney, liver, lung and pancreas. Skeletal muscle and heartwere of lower signal intensity.

HpTK5 expression in human tumor cell lines was also analyzed by Northernblot analysis performed as discussed above. Cell lines derived fromliver, breast (MCF 7), colon (Colo 205), lung (NCI 69), melanocyte(HM-1) or cervix (HeLa) had detectable signal of appropriate size.Message was present in select cell lines of hematopoietic origin. K562(a primitive myeloid cell with multipotential), THP-1 (a monocytoidcell), U937 (a myelomonocytic cell line), Hep3B (a human hepatocarcinomacell line), and CMK (of megakaryocytic origin) were all positive forHpTK5 message, but lymphoid (H9, Jurkat, JH-1, Raji, Ramos) or selectother myeloid cells (KG-1 or KMT2) had no detectable transcript byNorthern analysis.

Differential expression of the HpTK5 transcript in fetal versus adultbrain suggests that HpTK5 may share, with other EPH subfamily members, arole in events related to neural development. However, unlike somemembers of the EPH subfamily which are exclusively expressed in neurons(Maisonpierre et al., supra), HpTK5 is widely expressed in othertissues. In particular, HpTK5 is expressed in hematopoietic cellsincluding CD34+ hematopoietic progenitor cells. The presence of theHpTK5 message in early hematopoietic cells and cell lines of myeloidlineage, but not in cell lines derived from lymphoid cells, suggeststhat HpTK5 may have lineage restricted expression.

EXAMPLE 3 Production of Polyclonal Antibodies to HpTK5

An HpTK5 extracellular domain (ECD)-human IgG₁ Fc fusion gene wasconstructed and fusion protein produced as previously described (Bennettet al., J. Biol. Chem. 266:23060-23067 [1991]). Polyclonal antibodieswere generated in New Zealand White rabbits against the fusion protein;4 μg in 100 μL PBS was emulsified with 100 μL Freund's adjuvant(complete adjuvant for the primary injection and incomplete adjuvant forall boosts). For the primary immunization and the first boost, theprotein was injected directly into the popliteal lymph nodes (Sigel etal., Methods Enzymol. 93:3-12 [1983]). For subsequent boosts, theprotein was injected into subcutaneous and intramuscular sites. 1.3 μgprotein/kg body weight was injected every 3 weeks with bleeds taken 1and 2 weeks following each boost. HpTK5 specificity of the immunizedrabbit serum was assessed by flow cytometric analysis of NIH3T3 cellstransfected with full length HpTK5 or vector alone using a 1:200dilution of pre-immune serum or anti-HpTK5-IgG Fc serum. Significantpeak shifts were observed in several HpTK5 expressing clones as comparedto either pre-immune serum or vector alone transfectant controls.

EXAMPLE 4

Utility and Agonist Activity of Polyclonal Antibodies to HPTK5

A. FLAG-HpTK5 Fusion Construct

Overlapping oligonucleotides encoding a 12 amino acid peptide having thesequence MDYKDDDDKKLAM (SEQ ID NO: 41) which includes the 4 amino acidantibody recognition site “FLAG” (IBI, New Haven, Conn.) a 5′-EcoRVrestriction site and a 3′-NcoI restriction site(5′-CCGGATATCATGGACTACAAGGACGACGATGACAAGAAGCTTGCCATGGAGCTC; SEQ ID NO:42), were ligated into the NcoI site (base 88) of HpTK5 in the EcoRVdigested Bluescript (Stratagene, La Jolla, Calif.) vector.

B. In vitro Transcription and Translation

Transcription was performed on 2 pmol of linearized HpTK5 or FLAG-HpTK5containing plasmid at 37° C. for 1 h in 50 μl volume containing 10 mMdithiothreitol, 2.5 μg bovine serum albumin, 0.25 mM each dNTP, 0.5 Mm7GRNA cap (New England Biolabs, Beverly, Mass.), 2.5 units RNasin(Promega, Madison, Wis.), 3 units T3 RNA polymerase (Pharmacia,Piscataway, N.J.). 1 μg of DNAase (New England Biolabs, Beverly Mass.)was added for 15 min at 37° C. prior to phenol/chloroform extraction andethanol precipitation. Translation was performed using the Promegarabbit reticulocyte lysate kit according to the manufacturer'sspecifications with or without ³⁵S-methionine (350 μCi) labeling. Samplebuffer containing SDS and beta-mercaptoethanol (2-ME) was added beforeboiling and 10% SDS-PAGE.

C. HpTK5 Expression in NIH3T3 Cells

A 4038 bp Cla1-Xba1 cDNA fragment containing 32 bp of linker sequence,37 bp of pBluescript (Stratagene La Jolla, Calif.) polylinker and theentire 3969 bp HpTK5 cDNA was subcloned into the expression vector pRIS(Genentech, Inc.) under the control of the Rous sarcoma virus LTRpromoter. NIH3T3 cells maintained in high glucose Dulbecco's ModifiedEagle's Medium (DMEM) supplemented with 10% FCS were co-transfected withpRIS-HpTK5 and pNeo (an SV40 based vector containing the neomycinresistance marker) by the calcium phosphate method as described byGorman et al., in DNA Prot. Engineer. Tech. 2:3-10 [1990]. Neomycinresistant colonies were selected 48 hours after transfection withGeneticin (Gibco/BRL) at 400 μg/ml. Fourteen days later individualresistant colonies were isolated, expanded and analyzed by flowcytometry for HpTK5 expression using rabbit polyclonal antiserum.

D. Immunoprecioitation

Cells (Hep3B, control NIH3T3 or HpTK5 transfected NIH3T3) or in vitrotranslated protein (HpTK5 or FLAG-HpTK5) were used forimmunoprecipitation with either serum (pre-immune or anti-HpTK5-IgG Fc)or monoclonal antibody (FLAG-specific, M2, or isotype control) (IBI,Rochester, N.Y.). Subconfluent cells were labeled with 200 μCi/ml³⁵S-methionione for 18 hours and lysed in lysis buffer (150 mM NaCl, 50MTris-HCl pH8.0, 1 mM EDTA, 0.025 Na azide, 1% NP-40, 0.1% SDS, 10%Glycerol, 0.5% Na deoxycholate, 1 mM phenylmethylsulfonyl flouride(PMSF), 10 μg/ml aprotinin, 10 μg/ml leupeptin and 50 μM Na vanadate)for 30 min on ice. The cell lysate was centrifuged (12,000×g) for 10 minat 4° C. Cell lysate supernatant or in vitro translation mixture wasprecleared with 0.05 volume of normal rabbit serum and adsorbed with0.05 volume of Staphylococcus aureus protein-A Sepharose CL4B. Aftercentrifugation, preimmune or immune serum (1:100 dilution), ormonoclonal antibody, was added and rocked overnight at 4° C. before 100μl of protein-A Sepharose CL4B was added and the solution rocked 4° C.for additional 2 h. Immunoprecipitates were washed, suspended inSDS/PAGE loading buffer (109 glycerol, 5% 2-ME, 2.3% SDS and 62.5 mMTris-HCl pH 6.8), heated to 95° C. for 5 min and analyzed by 7.5%SDS-PAGE.

E. Cell Fractionation

Cell fractionation of Hep3B cells was performed to confirm the membranelocalization of HpTK5 predicted by its amino acid sequence. Hep-3B cells(1 ×10⁷) were labeled with 200 μCi/ml ³⁵S-methionine in alpha MEM mediumcontaining 10% dialyzed FCS overnight. The cells were washed twice withcold PBS, scraped into 1 ml of cold buffer (20 mM Tris-HCl pH 7.5, 2 mMEDTA, 5 mM EGTA, 0.25M sucrose, 0.01% leupeptin, 4 mM PMSF, 10 mM 2-ME)and disrupted by sonication for 40 seconds. Whole homogenates werecentrifuged at 12,000×g for 15 min, the nuclear pellets isolated and thedecanted supernatant centrifuged at 140,000×g for 40 min at 4° C. topellet membranes. The resultant supernatant served as the cytosolic (C)fraction. Nuclear (N) and membrane (M) fractions were washed anddissolved in buffer containing 0.5% NP-40 prior to immunoprecipitation.The C, N or M fractions were immunoprecipitated with an anti-HpTK5 orpre-immune (control) serum, subjected to 12% SDS-PAGE andautoradiographed. HpTK5 segregated predominantly with the membranefraction, though immunoprecipitated material was evident to a lesserextent in cytosol.

F. Protein Kinase Assay

Immunoprecipitates were washed once with kinase buffer (25 mM HepesH7.4, 1 mM DTT, 10 mM MgCl, 10 mM MnCl), and resuspended in 40 μl ofkinase buffer containing either unlabeled ATP or 10 μCi of ³²P-ATP (3000Ci/mM). After a 10 min incubation at 30° C., the reaction was stopped byadding 40 μl of 2×sample buffer and boiling the samples for 3 min priorto electrophoresis on 8.09% SDS-PAGE gel. The dried gel was covered with4 sheets of aluminum foil to block ³⁵S-labelled protein autoradiographyand the gel was placed under film for 5 hours to overnight.

G. Western Blotting and Phosphotyrosine Assay

Proteins were electrophoretically transferred to a 0.2 μm nitrocellulose(Bio-Rad) or a 0.45 μm polyvinylidene diflouride (Millipore) membrane ina buffer containing 25 mM Tris-HCl (pH 7.5), 192 mM glycine and 20%methanol at 100 mA for 2 h. Filters were washed in TBS (10 mM Tris-HClpH 8.0, 150 mM NaCl) blocked by incubating in TBST (TBS with 0.05%Tween-20) plus 5% BSA overnight. Filters were washed four times for 5min each in TEST and incubated for 2 h with 4G10 anti-phosphotyrosineantibody from UBI (1:1000 dilution in TBST). Filters were washed fourtimes for 5 min each in TBST and incubated for 1 h with the alkalinephosphatase labelled anti-mouse secondary antibody (Promega) at a 1:7500dilution in TBST. After washing four times, the blot was developed for30-60 min in AP buffer (100 mM Tris-HCl, 100 mM NaCl, 5 mM MgCl₂) plusBCIP, NBT substrates.

H. Antibody Induced Phosphorylation Assay

Rabbit antisera to HpTK5-IgG Fc were tested for their ability to induceHpTK5 phosphorylation in HPTK5 transfected NIH3T3 cells. Cells wereplated at a density of 5×10⁵ cells/well in a 6-well plate and, after 24hours, were serum starved for 1 hour prior to adding pre-immune orimmune serum at a 1:50 dilution for 30 minutes. Cells were then washedin PBS and lysed in either 2×sample buffer or NP-40 lysis buffer asdescribed above. Either crude lysates or immunoprecipitated cell lysateswere then separated via 4-12% gradient SDS-PAGE and analyzed byanti-phosphotyrosine immunoblot as described above. HpTK5 expressingcells were exposed to antisera and separated by SDS-PAGE either with orwithout immunoprecipitation. The electrotransferred gel wasimmunoblotted with anti-phosphotyrosine antibody. Enhanced tyrosinephosphorylation of HpTK5 was observed following exposure to polyclonalantiserum showing an agonist-like effect of antibody binding.Interaction of HpTK5 with an antibody directed against its ECD inducesphosphorylation. This provides further support that HpTK5 may serve as areceptor for a ligand that triggers kinase activation. Details of thesignaling pathway of HpTK5 may be further explored using antisera as asurrogate ligand.

I. Conclusions

An HpTK5 ECD-IgG Fc fusion protein was expressed, purified and used togenerate rabbit anti-serum which immunoprecipitated a 120 kD proteinfrom Hep3B cells. The specificity of the antiserum was confirmed byimmunoprecipitation of in vitro translated HpTK5 RNA and HpTK5transfected NIH3T3 cells. To determine the functional capacity of HpTK5,in vitro translated HpTK5 was immunoprecipitated, exposed to kinaseconditions and immunoblotted using a phosphotyrosine specific monoclonalantibody. The data obtained indicated that HpTK5 is phosphorylated ontyrosine. However, the presence of other bands consistently appearing inthe ³²P-labelled immunoprecipitation suggested that HpTK5 protein wasonly partially purified and therefore, it could not be concluded thatHpTK5 was enzymatically active. To overcome this problem, a fusionconstruct was generated in which an 8 amino acid epitope (FLAG) wasadded to the N-terminus of HpTK5. The FLAG-HpTK5 fusion was in vitrotranslated and immunoprecipitated with a FLAG-specific monoclonalantibody resulting in a single protein of appropriate size (˜120 kD).When subjected to kinase conditions in the presence of ³²P-ATP, theHpTK5-FLAG fusion protein was labelled on tyrosine confirming tyrosineautophosphorylation and thereby, the kinase function of HpTK5.

EXAMPLE 5 Production of Monoclonal Antibodies to HpTK5

Anti-HpTK5 monoclonal antibodies were produced by hyperimmunizing BALB/cmice intraperitoneally with the HpTK5 extracellular domain (ECD)-humanIgG₁ Fc fusion protein (produced using the techniques disclosed above)in RIBI adjuvant (RIBI ImmunoChem Research, Hamilton, Mont.) and fusingsplenocytes with the mouse myeloma cell line X63-Ag8.653 (Kearney etal., J. Immunol. 123:1548-1550 [1979]). The antibodies were purifiedfrom ascites fluid using protein A-Sepharose (Repligen Corp., Cambridge,Mass.) and established affinity chromatography methods (Goding, J. W.,J. Immunol. Methods 20:241-253 [1978]).

Monoclonal antibodies were screened for their ability to bind the HpTK5antigen. Starting on day 15 post fusion, culture supernatants wereharvested from the fusion plates and assayed for their ability tospecifically “capture” HpTK5-IgG. In this ELISA assay, goat anti-mouseIgG was coated onto 96 well microtiter plates. The culture supernatants(100 μl ) were added to the wells and the mouse IgG present was bound bythe goat anti-mouse IgG antibodies. The plates were washed and eitherHpTK5-IgG or CD4-IgG (100 μl at 6 nM) was added. The “captured”immunoadhesin was detected using a goat anti-hu (Fc specific)horseradish peroxidase conjugate and orthophenylene diamine substrate.Quantitation of substrate catalysis was determined by optical density at490 nm.

Agonist antibodies were then screened for using the techniques disclosedin Example 6 below. Two agonist monoclonal antibodies were identified,one of which has been deposited with the ATCC.

EXAMPLE 6 Agonist Activity of Monoclonal Antibodies to HpTK5

The monoclonal antibodies produced using the techniques disclosed inExample 5 were tested for their ability to induce HpTK5 phosphorylationin HpTK5 transfected NIH3T3 cells. Cells were plated at a density of5×10⁵ cells/well in a 6-well plate and, after 24 hours, were serumstarved for 1 hour prior to adding pre-immune serum or anti-HpTK5monoclonal antibody (undiluted conditioned hybridoma media was used) for30 minutes. Cells were then washed in PBS and lysed in either 2×samplebuffer or NP-40 lysis buffer as described above. Either crude lysates orimmunoprecipitated cell lysates were then separated via 4-12% gradientSDS-PAGE and analyzed by anti-phosphotyrosine immunoblot as describedabove. HpTK5 expressing cells were exposed to the monoclonal antibodyand separated by SDS-PAGE either with or without immunoprecipitation.The electrotransferred gel was immunoblotted with anti-phosphotyrosineantibody. Enhanced tyrosine phosphorylation of HpTK5 was observedfollowing exposure to monoclonal antibodies showing an agonist-likeeffect of antibody binding. Accordingly, interaction of HpTK5 with amonoclonal antibody directed against its ECD is able to inducephosphorylation of the kinase domain thereof.

EXAMPLE 7 Production of Polyclonal Antibodies to Sal-S1

A SAL-S1 extracellular domain (ECD)-human IgG₁ Fc fusion gene wasconstructed and fusion protein produced as previously described inBennett et al., J. Biol. Chem. 26:23060-23067 [1991]. Briefly, PCRprimers otk 1.41.1 (SEQ ID NO: 43) and otk 1.41.2 (SEQ ID NO: 44) wereemployed in the PCR technique using plasmid pRK5.tk1-1.1 (SEQ ID NO: 45)containing SAL-S1 nucleic acid as a template to create a DNA fragmentwhich, when digested with SalI/BstEII, generated an 155bp SalI/BstEIIfragment. This 155 bp fragment was combined with a 6839 bp SalI/HindIIIfragment isolated from pRK5.tk1-1.1 and a 719 bp BstEII/HindIII fragmentisolated from pBSSK-CH2-CH3 (Bennett et al., supra). These fragmentswere ligated together to create a plasmid pRK5.tk1.ig1.1 (7713 bp insize) which, when transfected into 293 cells, was used to produce aSAL-S1 extracellular domain (ECD)-human IgG Fc fusion protein. Fusionprotein was prepared and purified as described in Bennett et al., supra.Polyclonal antibodies were generated in female New Zealand White rabbitsagainst the fusion protein. Briefly, 12.5 μg of fusion protein in 0.625ml PBS was emulsified with 0.625 ml Freund's adjuvant (complete adjuvantfor the primary injection and incomplete adjuvant for all boosts). Theprimary injection and all boosts were intramuscular at two sites andsubcutaneous at multiple sites. Boosts were carried out at 3 weekintervals with bleeds taken 1 and 2 weeks following each boost. SAL-S1specificity of the immunized rabbit serum was assessed by flowcytometric analysis of 293 (ATCC CRL 1593) and COS7 (ATCC CRL 1651)cells transfected with full length SAL-S1 or vector alone (see below)using a 1:200 dilution of pre-immune serum or anti-SAL-S1-IgG Fc serum.Significant peak shifts were observed in several SAL-S1 expressingclones as compared to either pre-immune serum or vector alonetransfectant controls.

EXAMPLE 8 Utility and Agonist Activity of Sal-S1 Polyclonal Antibodies

A. Immunoprecipitation

Control 293 and COS7 cells as well as SAL-S1 transfected 293 and COS7cells were used for immunoprecipitation with either pre-immune serum oranti-SAL-S1-IgG Fc polyclonal antibody. COS7 and 293 cells weretransfected using a CaPO₄ procedure as described by Gorman, C. DNACloning, Glover D. Ed., IRL Press, Oxford, vol2: 143-190 (1985). Fortransient expression, 293 cells were transfected as described by Gearinget al. EMBO 8: 3667-3676 (1989). Subconfluent cells were labeled with200 μCi/ml ³⁵S- methionine for 18 hours and lysed in lysis buffer (150mM NaCl, 50 mM HEPES, pH 7.5, 1 mM EGTA, 0.025 Na azide, 1% Triton-X100, 1.5 mM MgCl₂, 10% Glycerol, 1 mM phenylmethylsulfonyl flouride[PMSF], 10 μg/ml aprotinin, 10 μg/ml leupeptin and 50 μM Na vanadate)for 10 min on ice. The cell lysate was centrifuged (12,000×g) for 10 minat 4° C. After centrifugation, preimmune or polyclonal antibody wasadded to the supernatant and rocked for 4 hrs at 4° C. before 100 μl ofprotein-A Sepharose CL4B was added and the solution rocked 4° C. foradditional 2 h. Immunoprecipitates were washed, suspended in SDS/PAGEloading buffer (10% glycerol, 5% 2-ME, 2.3% SDS and 62.5 mM Tris-HCl pH6.8), heated to 95° C. for 5 min and analyzed by 7.5% SDS-PAGE.

B. Western Blotting and Phosphotyrosine Assay

Proteins were electrophoretically transferred to a 0.2 μm nitrocellulose(Bio-Rad) or a 0.45 μm polyvinylidene diflouride (Millipore) membrane ina buffer containing 25 mM Tris-HCl (pH 7.5), 192 mM glycine and 20%methanol at 100 mA for 2 h. Filters were washed in TBS (10 mM Tris-HClpH 8.0, 150 mM NaCl) blocked by incubating in TBST (TBS with 0.05%Tween-20) plus 5% BSA overnight. Filters were washed four times for 5min each in TBST and incubated for 2 h with 4G10 anti-phosphotyrosineantibody from UBI (1:1000 dilution in TBST). Filters were washed fourtimes for 5 min each in TBST and incubated for 1 h with the alkalinephosphatase labelled anti-mouse secondary antibody (Promega) at a 1:5000dilution in TBST. After washing four times, the blot was developed for30-60 min in AP buffer (100 mM Tris-HCl, 100 mM NaCl, 5 mM MgCl₂) plusBCIP, NBT substrates.

C. Antibody Induced Phosphorylation Assay

Rabbit antisera to SAL-S1-IgG Fc were tested for their ability to induceSAL-S1 phosphorylation in SAL-S1 transfected 293 cells. Cells wereplated at a density of 5×10⁵ cells/well in a 6-well plate and, after 24hours, were serum starved for 12 hours prior to adding pre-immune orimmune serum at a 1:5 dilution for 30 minutes. Cells were then washed inPBS and lysed in either sample buffer or Triton-X lysis buffer asdescribed above. Either crude lysates or immunoprecipitated cell lysateswere then separated via 8% or 4-12% gradient SDS-PAGE and analyzed byanti-phosphotyrosine immunoblot as described above. SAL-S1 expressingcells were exposed to antisera and separated by SDS-PAGE either with orwithout immunoprecipitation. The electrotransferred gel wasimmunoblotted with anti-phosphotyrosine antibody. Enhanced tyrosinephosphorylation of SAL-S1 was observed following exposure to polyclonalantiserum showing an agonist-like effect of antibody binding.Interaction of SAL-S1 with an antibody directed against its ECD inducesphosphorylation.

EXAMPLE 9 Production of Monoclonal Antibodies to Sal-S1

Anti-SAL-S1 monoclonal antibodies were produced by hyperimmunizingBALB/c mice in the foot pad with the SAL-S1 extracellular domain-humanIgG₁ Fc fusion protein in RIBI adjuvant (RIBI Immunochem Research,Hamilton, Mont.) and fusing lymphocyte from lymph nodes with the mousemyeloma cell line X63-Ag8U1.

Starting on day 10 post fusion, cultured supernatants were harvest fromthe fusion plates and assayed for their ability to bind to SAL-S1. Inthis ELISA assay, SAL-S1 IgG₁ was coated onto 96 microtiter plates. Thecultured supernatants (100 μl) were added to the wells and the mouseantibodies present were bound to Sal-S1 IgG₁. The plates were washed andmouse IgG was detected using a goat anti-mouse IgG (Fc specific with nocross reactivity against human IgG Fc) horseradish peroxidase conjugateand orthophenylene diamine substrate. Quantitation of substratecatalysis was determined by optical density at 490 nm.

Cultured supernatants which were positive from ELISA were then testedfor their ability to specifically bind to 293 transfected with SAL-S1receptor and analyzed by flow cytometry. Agonist antibodies were thenscreened for using the techniques disclosed in Example 10 below. Sixagonist monoclonal antibodies were identified.

EXAMPLE 10 Agonist Activity of Monoclonal Antibodies to Sal-S1

The monoclonal antibodies were tested for their ability to induce SAL-S1phosphorylation in SAL-S1 transfected 293 cells. Cells were harvestedfrom tissue culture dish by assay buffer and washed 2×with the samebuffer. 1×10 ⁵ cells were added to a 96 U-bottom plate which wascentrifuged and assay buffer was removed. 150 μl of culturedsupernatants was added to each well followed by incubation at 37° C. for30 minutes, the plate was centrifuged and cultured supernatants wereremoved. 100 μl of Fixing solution was added, the cells were fixed for30 minutes at −20° C., cells were washed with buffer 2× and stained withanti-phosphotyrosine conjugate with FITC for 60 minutes at 4° C. Cellswere analyzed by flow cytometry (FACScan Becton Dickinson, Milplitas,Calif.). The six anti-SAL-S1 monoclonal antibodies were able to induceSAL-S1 phosphorylation in SAL-S1 transfected 293 cells.

Deposit of Materials

The following culture has been deposited with the American Type CultureCollection, 12301 Parklawn Drive, Rockville, Md., USA (ATCC):

Hybridoma ATCC No. Deposit Date Anti-HpTK5 HB 11,583 March 15, 1994

This deposit was made under the provisions of the Budapest Treaty on theInternational Recognition of the Deposit of Microorganisms for thePurpose of Patent Procedure and the Regulations thereunder (BudapestTreaty). This assures maintenance of a viable culture for 30 years fromthe date of deposit. The organism will be made available by ATCC underthe terms of the Budapest Treaty, and subject to an agreement betweenGenentech, Inc. and ATCC, which assures permanent and unrestrictedavailability of the progeny of the culture to the public upon issuanceof the pertinent U.S. patent or upon laying open to the public of anyU.S. or foreign patent application, whichever comes first, and assuresavailability of the progeny to one determined by the U.S. Commissionerof Patents and Trademarks to be entitled thereto according to 35 USC§122 and the Commissioner's rules pursuant thereto (including 37 CFR§1.14 with particular reference to 886 OG 638).

The assignee of the present application has agreed that if the cultureon deposit should die or be lost or destroyed when cultivated undersuitable conditions, it will be promptly replaced on notification with aviable specimen of the same culture. Availability of the depositedstrain is not to be construed as a license to practice the invention incontravention of the rights granted under the authority of anygovernment in accordance with its patent laws.

The foregoing written specification is considered to be sufficient toenable one skilled in the art to practice the invention. The presentinvention is not to be limited in scope by the culture deposited, sincethe deposited embodiment is intended as a single illustration of oneaspect of the invention and any culture that are functionally equivalentare within the scope of this invention. The deposit of material hereindoes not constitute an admission that the written description hereincontained is inadequate to enable the practice of any aspect of theinvention, including the best mode thereof, nor is it to be construed aslimiting the scope of the claims to the specific illustration that itrepresents. Indeed, various modifications of the invention in additionto those shown and described herein will become apparent to thoseskilled in the art from the foregoing description and fall within thescope of the appended claims.

Equivalents

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims.

45 17 base pairs Nucleic Acid Single Linear not provided 1 CGGATCCACAGNGACCT 17 23 base pairs Nucleic Acid Single Linear not provided 2GGAATTCCAA AGGACCAGAC GTC 23 21 base pairs Nucleic Acid Single Linearnot provided 3 CGGATCCATC CACAGAGATG T 21 26 base pairs Nucleic AcidSingle Linear not provided 4 GGAATTCCTT CAGGAGCCAT CCACTT 26 160 basepairs Nucleic Acid Single Linear not provided 5 GGATCCTGTG CATCAGTGACTTAGGGCTAG GAACATTCTG CTGTCGGAAA 50 GCGACGTGGT GAAGATCTGT GACTTTGGCCTTGCCCGGGA CATCTACAAA 100 GACCCCAGCT ACGTCCGCAA GCATGCCCGG CTGCCCCTGAAGTGGATGGC 150 GCCAGAATTC 160 53 amino acids Amino Acid Linear notprovided 6 Asp Pro Val His Gln Xaa Leu Arg Ala Arg Asn Ile Leu Leu Ser 15 10 15 Glu Ser Asp Val Val Lys Ile Cys Asp Phe Gly Leu Ala Arg Asp 2025 30 Ile Tyr Lys Asp Pro Ser Tyr Val Arg Lys His Ala Arg Leu Pro 35 4045 Leu Lys Trp Met Ala Pro Glu Phe 50 53 147 base pairs Nucleic AcidSingle Linear not provided 7 GGATCCATTC ACAGAGACCT AGCAGCACGC AACATCCTGGTCTCAGAGGA 50 CCTGGTAACC AAGGTCAGCG ACTTTGGCCT GGCCAAAGCC GAGCGGAAGG 100GGCTAGACTC AAGCCGGCTG CCCGTCAAAT GGATGGCTCC CGAATTC 147 49 amino acidsAmino Acid Linear not provided 8 Gly Ser Ile His Arg Asp Leu Ala Ala ArgAsn Ile Leu Val Ser 1 5 10 15 Glu Asp Leu Val Thr Lys Val Ser Asp PheGly Leu Ala Lys Ala 20 25 30 Glu Arg Lys Gly Leu Asp Ser Ser Arg Leu ProVal Lys Trp Met 35 40 45 Ala Pro Glu Phe 49 149 base pairs Nucleic AcidSingle Linear not provided 9 GTTGGAATTC CTTCCGGCGC CATCCATTTC ACCGGCAGCTTTATTTCGTG 50 TCTAGATTCA TAGATGTCTT CATTATCTAC CTTAAAAACT CTGGCAAGTC 100CAAAATCTGC TACTTTGTAG ATATTATGTT CACCAACGAG GACATTCCT 149 47 amino acidsAmino Acid Linear not provided 10 Val Gly Ile Pro Ser Gly Ala Ile HisPhe Thr Gly Ser Phe Ile 1 5 10 15 Ser Cys Leu Asp Ser Met Ser Ser LeuSer Thr Leu Lys Thr Leu 20 25 30 Ala Ser Pro Lys Ser Ala Thr Leu Ile LeuCys Ser Pro Thr Arg 35 40 45 Thr Phe 47 151 base pairs Nucleic AcidSingle Linear not provided 11 GTGCACAGGG ATCTCGCGGC TCGGAACATCCTCGTCGGGG AAAACACCCT 50 CTCGAAAGTT GGGGACTTCG GGTTAGCCAG GCTTATCAAGGAGGACGTCT 100 ACCTCTCCCA TGACCACAAT ATCCCCTACA AATGGATGGC CCCTGAGGGA150 A 151 50 amino acids Amino Acid Linear not provided 12 Val His ArgAsp Leu Ala Ala Arg Asn Ile Leu Val Gly Glu Asn 1 5 10 15 Thr Leu SerLys Val Gly Asp Phe Gly Leu Ala Arg Leu Ile Lys 20 25 30 Glu Asp Val TyrLeu Ser His Asp His Asn Ile Pro Tyr Lys Trp 35 40 45 Met Ala Pro Glu Gly50 137 base pairs Nucleic Acid Single Linear not provided 13 GTTCACCGAGATCTCAAGTC CAACAACATT TTGCTGCTGC AGCCCATTGA 50 GAGTGACGAC ATGGAGCACAAGACCCTGAA GATCACCGAC TTTGGCCTGG 100 CCCGAGAGTG GCACAAAACC ACACAAATGAGTGCCGC 137 45 amino acids Amino Acid Linear not provided 14 Val His ArgAsp Leu Lys Ser Asn Asn Ile Leu Leu Leu Gln Pro 1 5 10 15 Ile Glu SerAsp Asp Met Glu His Lys Thr Leu Lys Ile Thr Asp 20 25 30 Phe Gly Leu AlaArg Glu Trp His Lys Thr Thr Gln Met Ser Ala 35 40 45 211 base pairsNucleic Acid Single Linear not provided 15 GTCAATCGTG ACCTCGCCGCCCGAAATGTG TTGCTAGTTA CCCAACATTA 50 CGCCAAGATC AGTGATTTCG GACTTTCCAAAGCACTGCGT GCTGATGAAA 100 ACTACTACAA GGCCCAGACC CATGGAAAGT GGCCTGTCAAGTGGTACGCT 150 CCGGAATGCA TCAACTACTA CAAGTTCTCC AGCAAAAGCG ATGTCTGGTC200 CTTTGGAATT C 211 70 amino acids Amino Acid Linear not provided 16Val Asn Arg Asp Leu Ala Ala Arg Asn Val Leu Leu Val Thr Gln 1 5 10 15His Tyr Ala Lys Ile Ser Asp Phe Gly Leu Ser Lys Ala Leu Arg 20 25 30 AlaAsp Glu Asn Tyr Tyr Lys Ala Gln Thr His Gly Lys Trp Pro 35 40 45 Val LysTrp Tyr Ala Pro Glu Cys Ile Asn Tyr Tyr Lys Phe Ser 50 55 60 Ser Lys SerAsp Val Trp Ser Phe Gly Ile 65 70 6827 base pairs Nucleic Acid SingleLinear not provided 17 TTCGAGCTCG CCCGACATTG ATTATTGACT AGTTATTAATAGTAATCAAT 50 TACGGGGTCA TTAGTTCATA GCCCATATAT GGAGTTCCGC GTTACATAAC 100TTACGGTAAA TGGCCCGCCT GGCTGACCGC CCAACGACCC CCGCCCATTG 150 ACGTCAATAATGACGTATGT TCCCATAGTA ACGCCAATAG GGACTTTCCA 200 TTGACGTCAA TGGGTGGAGTATTTACGGTA AACTGCCCAC TTGGCAGTAC 250 ATCAAGTGTA TCATATGCCA AGTACGCCCCCTATTGACGT CAATGACGGT 300 AAATGGCCCG CCTGGCATTA TGCCCAGTAC ATGACCTTATGGGACTTTCC 350 TACTTGGCAG TACATCTACG TATTAGTCAT CGCTATTACC ATGGTGATGC400 GGTTTTGGCA GTACATCAAT GGGCGTGGAT AGCGGTTTGA CTCACGGGGA 450TTTCCAAGTC TCCACCCCAT TGACGTCAAT GGGAGTTTGT TTTGGCACCA 500 AAATCAACGGGACTTTCCAA AATGTCGTAA CAACTCCGCC CCATTGACGC 550 AAATGGGCGG TAGGCGTGTACGGTGGGAGG TCTATATAAG CAGAGCTCGT 600 TTAGTGAACC GTCAGATCGC CTGGAGACGCCATCCACGCT GTTTTGACCT 650 CCATAGAAGA CACCGGGACC GATCCAGCCT CCGCGGCCGGGAACGGTGCA 700 TTGGAACGCG GATTCCCCGT GCCAAGAGTG ACGTAAGTAC CGCCTATAGA750 GTCTATAGGC CCACTTGGCT TCGTTAGAAC GCGGCTACAA TTAATACATA 800ACCTTATGTA TCATACACAT ACGATTTAGG TGACACTATA GAATAACATC 850 CACTTTGCCTTTCTCTCCAC AGGTGTCCAC TCCCAGGTCC AACTGCACCT 900 CGGTTCTATC GATTGAATTCCCCGGGGATC CTCTAGAGAT CCCTCGACCT 950 CGAGATCCAT TGTGCTGGCG CGGATTCTTTATCACTGATA AGTTGGTGGA 1000 CATATTATGT TTATCAGTGA TAAAGTGTCA AGCATGACAAAGTTGCAGCC 1050 GAATACAGTG ATCCGTGCCG CCCTAGACCT GTTGAACGAG GTCGGCGTAG1100 ACGGTCTGAC GACACGCAAA CTGGCGGAAC GGTTGGGGGT TCAGCAGCCG 1150GCGCTTTACT GGCACTTCAG GAACAAGCGG GCGCTGCTCG ACGCACTGGC 1200 CGAAGCCATGCTGGCGGAGA ATCATAGCAC TTCGGTGCCG AGAGCCGACG 1250 ACGACTGGCG CTCATTTCTGACTGGGAATG CCCGCAGCTT CAGGCAGGCG 1300 CTGCTCGCCT ACCGCCAGCA CAATGGATCTCGAGGGATCT TCCATACCTA 1350 CCAGTTCTGC GCCTGCAGGT CGCGGCCGCA CTACTCTTTGATGTATTACT 1400 CATATTACCA AGGAATAACT GGCGGGCACA GGGTCAGGTG CTGAAGGGAC1450 ATTGTGAGAA GTGACCTAGA AGGCAAGAGG TGAGCCCTCT GTCACGCTGG 1500CATAAGGGCC GCTTGAGGGC TCTTTGGTCA AGCAGTAACG CCAGTGTCTG 1550 GGAAGGCACCTGTTACTCAG CAGACCATGA AAGGGCGTCT CCCTTTCCTT 1600 GGAGCAGTCA GGGAACACTCTGCTCCACCA GCTTCTTGTG GGAGCCTGGA 1650 TATTATCCAG GCCTGCCCGC AGTCATCCGGAGGCCTAACC CCTCCCTGTG 1700 GTGCTTCAGT GGTCACACTC CTTGTCCACT TTCATGCTCCTCTTGGCCTC 1750 CTGGTTCCTC TTGGAAGTTT GTAGTAGATA GCAGAAGAAA TAGCGAAAGT1800 CTTAAAGTCT TTGATCTTTC TTATAAGTGC AGAGAAGAAA TGCTGACGTA 1850TGCTGCCTTC TCTCTCTCTG CTTCAGCTAC CTGAAGCCGC TTTCTTGTCT 1900 ATACCTGCTCTCTATCTGCT CACACTCCTC CGAGGCCAGC ACCATCCCAC 1950 TGTCTGTCTG GTTGTCCACAGAGCCTTTGT AGGTCGTTGG GGTCATGGGG 2000 AATTCCTCAA ATGTCTTCAT CCTGGAGGAACCACGGGTCT CAGCCCCTCT 2050 GGCCAGGCAC CCGGGAAAGG ACACCCAGTT GTAATACCTGGCGGCCAGGC 2100 TGTGGCGCTG CAGGCTTGGC GGGCTGTCCT CAGCGTCAGC CTGGGCGATG2150 TGTAGGGCCA TGGTGGACAC CTGCGAGAAG CTGCCCTCTT CTGAGCTCTG 2200AGAGCTGCGC GGGGCCATGC AGACCTCCTC TTCCTCTTGC AGGCCCCTGC 2250 CCTGGAGCAGGTCCCCCAGG ATCTCCACCA GCTCCGAGAA TGCAGGTCTC 2300 GCCTTGGGGT CTCCGGACCAGCAGTTCAGC ATGATGCGGC GTATGGCGGG 2350 AGTGGCCAGC TCCGGGGCCC TCATCCTTGTGCCGTCTCTC AGCCGCTGGC 2400 AGAACTCCTC ATTGATCTGC ACCCCAGGGT ACGGGGAGGCCCCCAGAGAG 2450 AAGATCTCCC AGAGAAGCAC CCCAAAGGAC CACACGTCAC TCTGCGTGGT2500 GTACACCTTG TCGAAGATGC TTTCAGGGGC CATCCACTTC AGGGGCAGCC 2550GGGCACTGCC CTTGCGGACG TAGTCGGGGT CTTTGTAGAT GTCCCGGGCA 2600 AGGCCAAAGTCACAGATCTT CACCACGTCG CTTTCCGACA GCAGAATGTT 2650 CCGAGCAGCC AGGTCTCTGTGGATGCACTT TCGGGAAGCC AGGAACTCCA 2700 TCCCTCTGGC CACCTGGAAG CTGTAGCAGACAAGATCTTC CATGGTCAGC 2750 GGGCTCAGCC ACAGGTCCTC AGCTTCTTGG TCTGGAGAAGCCCGCCTCGC 2800 TCCGCCCTCG GTCTTCGAGA ACCGCGCGAA GAGGACCCTG TCGCTGCTCC2850 CCGGCCGCCT CCGATCCAGC CTGGCGAGCT CCACCATGGC GCGGAAGCGT 2900CCGCGCTGCT CGGGAGACTT CTCCTGCGGA TGCACGAAGC TGGCTCGAGG 2950 GCGCCCAGTCGTCCGCCGCA GAGGCGCCTC CATTCCCCCG CCGCCCGCGG 3000 CGCCCCGCAG GCCGCCCGCTCACCGNGCAG GGGCTGCGGC CGCGACTCTA 3050 GAGTCGACCT GCAGAAGCTT GGCCGCCATGGCCCAACTTG TTTATTGCAG 3100 CTTATAATGG TTACAAATAA AGCAATAGCA TCACAAATTTCACAAATAAA 3150 GCATTTTTTT CACTGCATTC TAGTTGTGGT TTGTCCAAAC TCATCAATGT3200 ATCTTATCAT GTCTGGATCG ATCGGGAATT AATTCGGCGC AGCACCATGG 3250CCTGAAATAA CCTCTGAAAG AGGAACTTGG TTAGGTACCT TCTGAGGCGG 3300 AAAGAACCAGCTGTGGAATG TGTGTCAGTT AGGGTGTGGA AAGTCCCCAG 3350 GCTCCCCAGC AGGCAGAAGTATGCAAAGCA TGCATCTCAA TTAGTCAGCA 3400 ACCAGGTGTG GAAAGTCCCC AGGCTCCCCAGCAGGCAGAA GTATGCAAAG 3450 CATGCATCTC AATTAGTCAG CAACCATAGT CCCGCCCCTAACTCCGCCCA 3500 TCCCGCCCCT AACTCCGCCC AGTTCCGCCC ATTCTCCGCC CCATGGCTGA3550 CTAATTTTTT TTATTTATGC AGAGGCCGAG GCCGCCTCGG CCTCTGAGCT 3600ATTCCAGAAG TAGTGAGGAG GCTTTTTTGG AGGCCTAGGC TTTTGCAAAA 3650 AGCTGTTAACAGCTTGGCAC TGGCCGTCGT TTTACAACGT CGTGACTGGG 3700 AAAACCCTGG CGTTACCCAACTTAATCGCC TTGCAGCACA TCCCCCCTTC 3750 GCCAGCTGGC GTAATAGCGA AGAGGCCCGCACCGATCGCC CTTCCCAACA 3800 GTTGCGTAGC CTGAATGGCG AATGGCGCCT GATGCGGTATTTTCTCCTTA 3850 CGCATCTGTG CGGTATTTCA CACCGCATAC GTCAAAGCAA CCATAGTACG3900 CGCCCTGTAG CGGCGCATTA AGCGCGGCGG GTGTGGTGGT TACGCGCAGC 3950GTGACCGCTA CACTTGCCAG CGCCCTAGCG CCCGCTCCTT TCGCTTTCTT 4000 CCCTTCCTTTCTCGCCACGT TCGCCGGCTT TCCCCGTCAA GCTCTAAATC 4050 GGGGGCTCCC TTTAGGGTTCCGATTTAGTG CTTTACGGCA CCTCGACCCC 4100 AAAAAACTTG ATTTGGGTGA TGGTTCACGTAGTGGGCCAT CGCCCTGATA 4150 GACGGTTTTT CGCCCTTTGA CGTTGGAGTC CACGTTCTTTAATAGTGGAC 4200 TCTTGTTCCA AACTGGAACA ACACTCAACC CTATCTCGGG CTATTCTTTT4250 GATTTATAAG GGATTTTGCC GATTTCGGCC TATTGGTTAA AAAATGAGCT 4300GATTTAACAA AAATTTAACG CGAATTTTAA CAAAATATTA ACGTTTACAA 4350 TTTTATGGTGCACTCTCAGT ACAATCTGCT CTGATGCCGC ATAGTTAAGC 4400 CAACTCCGCT ATCGCTACGTGACTGGGTCA TGGCTGCGCC CCGACACCCG 4450 CCAACACCCG CTGACGCGCC CTGACGGGCTTGTCTGCTCC CGGCATCCGC 4500 TTACAGACAA GCTGTGACCG TCTCCGGGAG CTGCATGTGTCAGAGGTTTT 4550 CACCGTCATC ACCGAAACGC GCGAGGCAGT ATTCTTGAAG ACGAAAGGGC4600 CTCGTGATAC GCCTATTTTT ATAGGTTAAT GTCATGATAA TAATGGTTTC 4650TTAGACGTCA GGTGGCACTT TTCGGGGAAA TGTGCGCGGA ACCCCTATTT 4700 GTTTATTTTTCTAAATACAT TCAAATATGT ATCCGCTCAT GAGACAATAA 4750 CCCTGATAAA TCTTCAATAATATTGAAAAA GGAAGAGTAT GAGTATTCAA 4800 ACATTTCCGT GTCGCCCTTA TTCCCTTTTTGGCGGCATTT TGCCTTCCTG 4850 TTTTTGCTCA CCCAGAAACG CTGGTGAAAG TAAAAGATGCTGAAGATCAG 4900 TTGGGTGCAC GAGTGGGTTA CATCGAACTG GATCTCAACA GCGGTAAGAT4950 CCTTGAGAGT TTTCGCCCCG AAGAACGTTT TCCAATGATG AGCACTTTTA 5000AAGTTCTGCT ATGTGGCGCG GTATTATCCC GTGATGACGC CGGGCAAGAG 5050 CAACTCGGTCGCCGCATACA CTATTCTCAG AATGACTTGG TTGAGTACTC 5100 ACCAGTCACA GAAAAGCATCTTACGGATGG CATGACAGTA AGAGAATTAT 5150 GCAGTGCTGC CATAACCATG AGTGATAACACTGCGGCCAA CTTACTTCTG 5200 ACAACGATCG GAGGACCGAA GGAGCTAACC GCTTTTTTGCACAACATGGG 5250 GGATCATGTA ACTCGCCTTG ATCGTTGGGA ACCGGAGCTG AATGAAGCCA5300 TACCAAACGA CGAGCGTGAC ACCACGATGC CAGCAGCAAT GGCAACAACG 5350TTGCGCAAAC TATTAACTGG CGAACTACTT ACTCTAGCTT CCCGGCAACA 5400 ATTAATAGACTGGATGGAGG CGGATAAAGT TGCAGGACCA CTTCTGCGCT 5450 CGGCCCTTCC GGCTGGCTGGTTTATTGCTG ATAAATCTGG AGCCGGTGAG 5500 CGTGGGTCTC GCGGTATCAT TGCAGCACTGGGGCCAGATG GTAAGCCCTC 5550 CCGTATCGTA GTTATCTACA CGACGGGGAG TCAGGCAACTATGGATGAAC 5600 GAAATAGACA GATCGCTGAG ATAGGTGCCT CACTGATTAA GCATTGGTAA5650 CTGTCAGACC AAGTTTACTC ATATATACTT TAGATTGATT TAAAACTTCA 5700TTTTTAATTT AAAAGGATCT AGGTGAAGAT CCTTTTTGAT AATCTCATGA 5750 CCAAAATCCCTTAACGTGAG TTTTCGTTCC ACTGAGCGTC AGACCCCGTA 5800 GAAAAGATCA AAGGATCTTCTTGAGATCCT TTTTTTCTGC GCGTAATCTG 5850 CTGCTTGCAA ACAAAAAAAC CACCGCTACCAGCGGTGGTT TGTTTGCCGG 5900 ATCAAGAGCT ACCAACTCTT TTTCCGAAGG TAACTGGCTTCAGCAGAGCG 5950 CAGATACCAA ATACTGTCCT TCTAGTGTAG CCGTAGTTAG GCCACCACTT6000 CAAGAACTCT GTAGCACCGC CTACATACCT CGCTCTGCTA ATCCTGTTAC 6050CAGTGGCTGC TGCCAGTGGC GATAAGTCGT GTCTTACCGG GTTGGACTCA 6100 AGACGATAGTTACCGGATAA GGCGCAGCGG TCGGGCTGAA CCGGGGGTTC 6150 GTGCACACAG CCCAGCTTGGAGCGAACGAC CTACACCGAA CTGAGATACC 6200 TACAGCGTGA GCATTGAGAA AGCGCCACGCTTCCCGAAGG GAGAAAGGCG 6250 GACAGGTATC CGGTAAGCGG CAGGGTCGGA ACAGGAGAGCGCACGAGGGA 6300 GCTTCCAGGG GGAAACGCCT GGTATCTTTA TAGTCCTGTC GGGTTTCGCC6350 ACCTCTGACT TGAGCGTCGA TTTTTGTGAT GCTCGTCAGG GGGGCGGAGC 6400CTATGGAAAA ACGCCAGCAA CGCGGCCTTT TTACGGTTCC TGGCCTTTTG 6450 CTGGCCTTTTGCTCACATGT TCTTTCCTGC GTTATCCCCT GATTCTGTGG 6500 ATAACCGTAT TACCGCCTTTGAGTGAGCTG ATACCGCTCG CCGCAGCCGA 6550 ACGACCGAGC GCAGCGAGTC AGTGAGCGAGGAAGCGGAAG AGCGCCCAAT 6600 ACGCAAACCG CCTCTCCCCG CGCGTTGGCC GATTCATTAATCCAGCTGGC 6650 ACGACAGGTT TCCCGACTGG AAAGCGGGCA GTGAGCGCAA CGCAATTAAT6700 GTGAGTTACC TCACTCATTA GGCACCCCAG GCTTTACACT TTATGCTTCC 6750GGCTCGTATG TTGTGTGGAA TTGTGAGCGG ATAACAATTT CACACAGGAA 6800 ACAGCTATGACCATGATTAC GAATTAA 6827 348 amino acids Amino Acid Linear not provided18 Glu Lys Ser Pro Glu Gln Arg Gly Arg Phe Arg Ala Met Val Glu 1 5 10 15Leu Ala Arg Leu Asp Arg Arg Arg Pro Gly Ser Ser Asp Arg Val 20 25 30 LeuPhe Ala Arg Phe Ser Lys Thr Glu Gly Gly Ala Arg Arg Ala 35 40 45 Ser ProAsp Gln Glu Ala Glu Asp Leu Trp Leu Ser Pro Leu Thr 50 55 60 Met Glu AspLeu Val Cys Tyr Ser Phe Gln Val Ala Arg Gly Met 65 70 75 Glu Phe Leu AlaSer Arg Lys Cys Ile His Arg Asp Leu Ala Ala 80 85 90 Arg Asn Ile Leu LeuSer Glu Ser Asp Val Val Lys Ile Cys Asp 95 100 105 Phe Gly Leu Ala ArgAsp Ile Tyr Lys Asp Pro Asp Tyr Val Arg 110 115 120 Lys Gly Ser Ala ArgLeu Pro Leu Lys Trp Met Ala Pro Glu Ser 125 130 135 Ile Phe Asp Lys ValTyr Thr Thr Gln Ser Asp Val Trp Ser Phe 140 145 150 Gly Val Leu Leu TrpGlu Ile Phe Ser Leu Gly Ala Ser Pro Tyr 155 160 165 Pro Gly Val Gln IleAsn Glu Glu Phe Cys Gln Arg Leu Arg Asp 170 175 180 Gly Thr Arg Met ArgAla Pro Glu Leu Ala Thr Pro Ala Ile Arg 185 190 195 Arg Ile Met Leu AsnCys Trp Ser Gly Asp Pro Lys Ala Arg Pro 200 205 210 Ala Phe Ser Glu LeuVal Glu Ile Leu Gly Asp Leu Leu Gln Gly 215 220 225 Arg Gly Leu Gln GluGlu Glu Glu Val Cys Met Ala Pro Arg Ser 230 235 240 Ser Gln Ser Ser GluGlu Gly Ser Phe Ser Gln Val Ser Thr Met 245 250 255 Ala Leu His Ile AlaGln Ala Asp Ala Glu Asp Ser Pro Pro Ser 260 265 270 Leu Gln Arg His SerLeu Ala Ala Arg Tyr Tyr Asn Trp Val Ser 275 280 285 Phe Pro Gly Cys LeuAla Arg Gly Ala Glu Thr Arg Gly Ser Ser 290 295 300 Arg Met Lys Thr PheGlu Glu Phe Pro Met Thr Pro Thr Thr Tyr 305 310 315 Lys Gly Ser Val AspAsn Gln Thr Asp Ser Gly Met Val Leu Ala 320 325 330 Ser Glu Glu Cys GluGln Ile Glu Ser Arg Tyr Arg Gln Glu Ser 335 340 345 Gly Phe Arg 348 7607base pairs Nucleic Acid Single Linear not provided 19 TTCGAGCTCGCCCGACATTG ATTATTGACT AGTTATTAAT AGTAATCAAT 50 TACGGGGTCA TTAGTTCATAGCCCATATAT GGAGTTCCGC GTTACATAAC 100 TTACGGTAAA TGGCCCGCCT GGCTGACCGCCCAACGACCC CCGCCCATTG 150 ACGTCAATAA TGACGTATGT TCCCATAGTA ACGCCAATAGGGACTTTCCA 200 TTGACGTCAA TGGGTGGAGT ATTTACGGTA AACTGCCCAC TTGGCAGTAC250 ATCAAGTGTA TCATATGCCA AGTACGCCCC CTATTGACGT CAATGACGGT 300AAATGGCCCG CCTGGCATTA TGCCCAGTAC ATGACCTTAT GGGACTTTCC 350 TACTTGGCAGTACATCTACG TATTAGTCAT CGCTATTACC ATGGTGATGC 400 GGTTTTGGCA GTACATCAATGGGCGTGGAT AGCGGTTTGA CTCACGGGGA 450 TTTCCAAGTC TCCACCCCAT TGACGTCAATGGGAGTTTGT TTTGGCACCA 500 AAATCAACGG GACTTTCCAA AATGTCGTAA CAACTCCGCCCCATTGACGC 550 AAATGGGCGG TAGGCGTGTA CGGTGGGAGG TCTATATAAG CAGAGCTCGT600 TTAGTGAACC GTCAGATCGC CTGGAGACGC CATCCACGCT GTTTTGACCT 650CCATAGAAGA CACCGGGACC GATCCAGCCT CCGCGGCCGG GAACGGTGCA 700 TTGGAACGCGGATTCCCCGT GCCAAGAGTG ACGTAAGTAC CGCCTATAGA 750 GTCTATAGGC CCACTTGGCTTCGTTAGAAC GCGGCTACAA TTAATACATA 800 ACCTTATGTA TCATACACAT ACGATTTAGGTGACACTATA GAATAACATC 850 CACTTTGCCT TTCTCTCCAC AGGTGTCCAC TCCCAGGTCCAACTGCACCT 900 CGGTTCTATC GATTGAATTC CCCGGGGATC CTCTAGAGAT CCCTCGACCT950 CGAGTCGACT TTTTTTTTTT TTTTTGTAGG CCAAAGGGTA CTTCTTTTTC 1000TTTATTAATT ACTCAGAAGT CTAGGCCACA GCAATCTACT GTTCTCCTCT 1050 CATTTTCCTAAACTATTTTG ATACCTATTT CTCAGACTTT ATGGGCTATT 1100 AGACATTTCT CACATTTCCATAGATAATAA CTCATCCGTT TTGCAACCTG 1150 ATTCTCAATA TTAAGAGATT AAAACTAATGTATATGACTC TCAGTTGACA 1200 CATACTGAAG TACAGAAAAA TTCCATCATT TCCTTCTGCAAAATGAAAAA 1250 GACTTCGTTT TCTCAACAGC TGCATCATTT TTTTATGCAT AGAAAAAAAT1300 GTGCAATTAC TCCAAGTACA ATCAAGTCAT TTAACATGGC TTTACCATCA 1350TTGTAGTTAC AGGATATTTT AAAAGAGAAA AAAAAATCTC AAAGCACAGG 1400 TCCTGCTGTGCAGCAAAGCA ATCAAATTCC TTCATAATAA CAGCCTGATG 1450 GGATTCAGCA ATCTGAGGAATAATGAATAA CCACTCTAAT CAGTAAACAG 1500 GAAAATGCTA CAACAGTCAC TGAGTAAAAATTGGACTATC ATCTGTTGAT 1550 TCTCTTGATC GACATTTCAA ACAATAAATG GAAATGTAAGTATCTCTTAA 1600 AAAGAAAAAT AACTTGGTTT AGTGTGCTTA ATTTTACCAG GCAGTGAGGA1650 AATTATATAT CACCTTGACT GTCCTGCAGT GTTGCCCAGT CAATAAAATG 1700CACAAATAAT CTTTTTCATA ATACATGGCC AACTTTATCC TATCACTTGA 1750 ATATGTCAGGATAAACTGAT TGTGCAGTTG GTTGATAACA TTGTATTTTG 1800 GAATGGATTA TTTGAATTTGTTTTGCTACT TTATTATTTG ATATTCTTCT 1850 CCAGTGTTCA TCTTATGAAG TTATTTGCATCTGAATATGA AGAGTCTGTT 1900 TCAAAATAGT CTTCAAGTTT CCAACGCAGT GTCTCAAATGTAGGTCGTTC 1950 CTTAGGCTCT GCATTCCAGC ACTCCAACAT GATGTTGTAA AATTGCTGTG2000 GACAGTTGGA TGGTTGCGGA AGTCTATAGT TTTGAGCCAA CATCTGGATT 2050ACCTGGGCAC CTGTCATACC ACTGTAAGGC ATTTTGCCAT AAGTAATGAT 2100 TTCATAAAGAAGGATTCCAA ATGACCATAC ATCGGACTTA ATGCTGAATT 2150 TATTACTACG AATGGCTTCGGGCGCAGTCC ACTTCACCGG CAGCTTTATT 2200 TCGTGTCTAG ATTCATAGAT GTCTTCATTATCTACCTTAA AAACTCTGGC 2250 AAGTCCAAAA TCTGCTACTT TGTAGATATT ATGTTCACCAACGAGGACAT 2300 TTCTGGCAGC CAGATCTCTG TGAATGTAGT TCCGAGACTC CAGATAGGCC2350 ATTCCAGAGG CAACCTGTGC CGCCATGTCT ACCTGTTGAG TCAGATGGAT 2400TTTTGATCCA GTGTCATTTT GGAGATATTC TTGCAGACTT CCATGTCTCA 2450 TCAACTCTGTAATAATATAA ATTGGATCTT CTAAAGTGCA AACAGCATAA 2500 AGCTGGATAA GCTTTGGATGTCTTAGGTTC TTCATTATCT GTGCCTCCCT 2550 CAGGAAGTCA TTTGGATCCA TTGAACCTGGTTTTAATGTT TTCACTGCTA 2600 CTGGAGTGGT ATTGTTCCAC AGACCTTCCC ATACTTCGCCAAACTGACCA 2650 GATCCCAATC GCTTCAGAAG CTGTATGGAG TTGCGGTCTA TCTCCCATTG2700 GTCCACGGTT TTATACGACA AATCAAATGG AGCTGGGACC TGGATCTTTA 2750AGCATGGTTT CCCCAGCTTG ACACACAGGC CGTCACTTGT CTTGGTGTAG 2800 TGGCTCACAAATTCGTTCAG TGTTGAAAAG ATTCTTCTTC GCGTGAGAAA 2850 AAATCCCCCT TCATCCAGTCTTTTAATTCT GTAGTGTTTT ACAACTGCTC 2900 CATCTAAAAC TGAAAGAGAG AATTCTCCTTTTTGGCTTTC ACTTTCTCTG 2950 ATTAGAAAGG AACCGGTCTT GTTTTCTGAA TATAATAGTTGTTTCTCTGC 3000 ATCTGATCTT CCGATTGCTC CAAAGAACCA CGGCTCTGCC TGTAGGCTTC3050 TGTCCTCAGC CACGTAGTTA GAAGGAATAT AGCCTTGTAG TTGCTGACTG 3100GAGCCATCTC GTCTTTTCTC CAAGTGTCTG GCAAACCACC AGCCCTCATG 3150 CAAAGTGTCCAGAACTTGAA GTTTGTCACC TGCTCGGAAG CTCAAGTCCT 3200 CAGCAGTCCG AGCCTGGTAATCAAACAAAG CCACAAAGTA GTGGCCATGC 3250 CTCTGTGACT GGGGAGAGCA AAGGGCCCCTGGATTTTCAA TCACGGTTGA 3300 CTTGTCTGCC TCCGTGGACA AACAGGGGAG ATAGGGTTCTAGGTACTCCC 3350 AGAGCCTCTG ACAGATGTTG CTCATTGTGC CTTGGTGGGG AGAAGAGGAG3400 CAGGGCTTCT CCCTCTCCCC TTAGTCTCTG CGATCCACCT TATCTTCCTT 3450CACCAGGCAA CTTTGAAGTC AGCACCAACT CACCATACTT CGGAGAGTAT 3500 GCAAAGTCCCGTTTCAGATC AGTCCAGCAG CTGGGTTGCA GCAAGTCCTA 3550 CCTGGAGAGA CTTACCGGCTTGCTTTCTGT GGCTGGAGGT GCTACCCCGA 3600 GGCAAAACTG AGCAGGAGCT GGGCAGCTGCTCACTAGGAA GGTGTCTTTT 3650 CTTCTTATCT GCTTAAGAAT CCCACAACAA AAATAAAATAAAATTAAAAG 3700 GGCTTTATTT AGACAAATAT CTGAGAACAG AATGGTGCCA TCTTGCCTTT3750 TGTCCCAATA AAAAGTTAGC AAGAGGAAGC TACTAACCCC TGGTAAAACC 3800TCCACGTCTT GCTTTCGCCA GGGTCGACTC GAGGGATCTT CCATACCTAC 3850 CAGTTCTGCGCCTGCAGGTC GCGGCCGCGA CTCTAGAGTC GACCTGCAGA 3900 AGCTTGGCCG CCATGGCCCAACTTGTTTAT TGCAGCTTAT AATGGTTACA 3950 AATAAAGCAA TAGCATCACA AATTTCACAAATAAAGCATT TTTTTCACTG 4000 CATTCTAGTT GTGGTTTGTC CAAACTCATC AATGTATCTTATCATGTCTG 4050 GATCGGGAAT TAATTCGGCG CAGCACCATG GCCTGAAATA ACCTCTGAAA4100 GAGGAACTTG GTTAGGTACC TTCTGAGGCG GAAAGAACCA GCTGTGGAAT 4150GTGTGTCAGT TAGGGTGTGG AAAGTCCCCA GGCTCCCCAG CAGGCAGAAG 4200 TATGCAAAGCATGCATCTCA ATTAGTCAGC AACCAGGTGT GGAAAGTCCC 4250 CAGGCTCCCC AGCAGGCAGAAGTATGCAAA GCATGCATCT CAATTAGTCA 4300 GCAACCATAG TCCCGCCCCT AACTCCGCCCATCCCGCCCC TAACTCCGCC 4350 CAGTTCCGCC CATTCTCCGC CCCATGGCTG ACTAATTTTTTTTATTTATG 4400 CAGAGGCCGA GGCCGCCTCG GCCTCTGAGC TATTCCAGAA GTAGTGAGGA4450 GGCTTTTTTG GAGGCCTAGG CTTTTGCAAA AAGCTGTTAA CAGCTTGGCA 4500CTGGCCGTCG TTTTACAACG TCGTGACTGG GAAAACCCTG GCGTTACCCA 4550 ACTTAATCGCCTTGCAGCAC ATCCCCCTTT CGCCAGCTGG CGTAATAGCG 4600 AAGAGGCCCG CACCGATCGCCCTTCCCAAC AGTTGCGCAG CCTGAATGGC 4650 GAATGGCGCC TGATGCGGTA TTTTCTCCTTACGCATCTGT GCGGTATTTC 4700 ACACCGCATA CGTCAAAGCA ACCATAGTAC GCGCCCTGTAGCGGCGCATT 4750 AAGCGCGGCG GGTGTGGTGG TTACGCGCAG CGTGACCGCT ACACTTGCCA4800 GCGCCCTAGC GCCCGCTCCT TTCGCTTTCT TCCCTTCCTT TCTCGCCACG 4850TTCGCCGGCT TTCCCCGTCA AGCTCTAAAT CGGGGGCTCC CTTTAGGGTT 4900 CCGATTTAGTGCTTTACGGC ACCTCGACCC CAAAAAACTT GATTTGGGTG 4950 ATGGTTCACG TAGTGGGCCATCGCCCTGAT AGACGGTTTT TCGCCCTTTG 5000 ACGTTGGAGT CCACGTTCTT TAATAGTGGACTCTTGTTCC AAACTGGAAC 5050 AACACTCAAC CCTATCTCGG GCTATTCTTT TGATTTATAAGGGATTTTGC 5100 CGATTTCGGC CTATTGGTTA AAAAATGAGC TGATTTAACA AAAATTTAAC5150 GCGAATTTTA ACAAAATATT AACGTTTACA ATTTTATGGT GCACTCTCAG 5200TACAATCTGC TCTGATGCCG CATAGTTAAG CCAGCCCCGA CACCCGCCAA 5250 CACCCGCTGACGCGCCCTGA CGGGCTTGTC TGCTCCCGGC ATCCGCTTAC 5300 AGACAAGCTG TGACCGTCTCCGGGAGCTGC ATGTGTCAGA GGTTTTCACC 5350 GTCATCACCG AAACGCGCGA GACGAAAGGGCCTCGTGATA CGCCTATTTT 5400 TATAGGTTAA TGTCATGATA ATAATGGTTT CTTAGACGTCAGGTGGCACT 5450 TTTCGGGGAA ATGTGCGCGG AACCCCTATT TGTTTATTTT TCTAAATACA5500 TTCAAATATG TATCCGCTCA TGAGACAATA ACCCTGATAA ATGCTTCAAT 5550AATATTGAAA AAGGAAGAGT ATGAGTATTC AACATTTCCG TGTCGCCCTT 5600 ATTCCCTTTTTTGCGGCATT TTGCCTTCCT GTTTTTGCTC ACCCAGAAAC 5650 GCTGGTGAAA GTAAAAGATGCTGAAGATCA GTTGGGTGCA CGAGTGGGTT 5700 ACATCGAACT GGATCTCAAC AGCGGTAAGATCCTTGAGAG TTTTCGCCCC 5750 GAAGAACGTT TTCCAATGAT GAGCACTTTT AAAGTTCTGCTATGTGGCGC 5800 GGTATTATCC CGTATTGACG CCGGGCAAGA GCAACTCGGT CGCCGCATAC5850 ACTATTCTCA GAATGACTTG GTTGAGTACT CACCAGTCAC AGAAAAGCAT 5900CTTACGGATG GCATGACAGT AAGAGAATTA TGCAGTGCTG CCATAACCAT 5950 GAGTGATAACACTGCGGCCA ACTTACTTCT GACAACGATC GGAGGACCGA 6000 AGGAGCTAAC CGCTTTTTTGCACAACATGG GGGATCATGT AACTCGCCTT 6050 GATCGTTGGG AACCGGAGCT GAATGAAGCCATACCAAACG ACGAGCGTGA 6100 CACCACGATG CCTGTAGCAA TGGCAACAAC GTTGCGCAAACTATTAACTG 6150 GCGAACTACT TACTCTAGCT TCCCGGCAAC AATTAATAGA CTGGATGGAG6200 GCGGATAAAG TTGCAGGACC ACTTCTGCGC TCGGCCCTTC CGGCTGGCTG 6250GTTTATTGCT GATAAATCTG GAGCCGGTGA GCGTGGGTCT CGCGGTATCA 6300 TTGCAGCACTGGGGCCAGAT GGTAAGCCCT CCCGTATCGT AGTTATCTAC 6350 ACGACGGGGA GTCAGGCAACTATGGATGAA CGAAATAGAC AGATCGCTGA 6400 GATAGGTGCC TCACTGATTA AGCATTGGTAACTGTCAGAC CAAGTTTACT 6450 CATATATACT TTAGATTGAT TTAAAACTTC ATTTTTAATTTAAAAGGATC 6500 TAGGTGAAGA TCCTTTTTGA TAATCTCATG ACCAAAATCC CTTAACGTGA6550 GTTTTCGTTC CACTGAGCGT CAGACCCCGT AGAAAAGATC AAAGGATCTT 6600CTTGAGATCC TTTTTTTCTG CGCGTAATCT GCTGCTTGCA AACAAAAAAA 6650 CCACCGCTACCAGCGGTGGT TTGTTTGCCG GATCAAGAGC TACCAACTCT 6700 TTTTCCGAAG GTAACTGGCTTCAGCAGAGC GCAGATACCA AATACTGTTC 6750 TTCTAGTGTA GCCGTAGTTA GGCCACCACTTCAAGAACTC TGTAGCACCG 6800 CCTACATACC TCGCTCTGCT AATCCTGTTA CCAGTGGCTGCTGCCAGTGG 6850 CGATAAGTCG TGTCTTACCG GGTTGGACTC AAGACGATAG TTACCGGATA6900 AGGCGCAGCG GTCGGGCTGA ACGGGGGGTT CGTGCACACA GCCCAGCTTG 6950GAGCGAACGA CCTACACCGA ACTGAGATAC CTACAGCGTG AGCTATGAGA 7000 AAGCGCCACGCTTCCCGAAG GGAGAAAGGC GGACAGGTAT CCGGTAAGCG 7050 GCAGGGTCGG AACAGGAGAGCGCACGAGGG AGCTTCCAGG GGGAAACGCC 7100 TGGTATCTTT ATAGTCCTGT CGGGTTTCGCCACCTCTGAC TTGAGCGTCG 7150 ATTTTTGTGA TGCTCGTCAG GGGGGCGGAG CCTATGGAAAAACGCCAGCA 7200 ACGCGGCCTT TTTACGGTTC CTGGCCTTTT GCTGGCCTTT TGCTCACATG7250 TTCTTTCCTG CGTTATCCCC TGATTCTGTG GATAACCGTA TTACCGCCTT 7300TGAGTGAGCT GATACCGCTC GCCGCAGCCG AACGACCGAG CGCAGCGAGT 7350 CAGTGAGCGAGGAAGCGGAA GAGCGCCCAA TACGCAAACC GCCTCTCCCC 7400 GCGCGTTGGC CGATTCATTAATGCAGCTGG CACGACAGGT TTCCCGACTG 7450 GAAAGCGGGC AGTGAGCGCA ACGCAATTAATGTGAGTTAG CTCACTCATT 7500 AGGCACCCCA GGCTTTACAC TTTATGCTTC CGGCTCGTATGTTGTGTGGA 7550 ATTGTGAGCG GATAACAATT TCACACAGGA AACAGCTATG ACATGATTAC7600 GAATTAA 7607 505 amino acids Amino Acid Linear not provided 20 MetSer Asn Ile Cys Gln Arg Leu Trp Glu Tyr Leu Glu Pro Tyr 1 5 10 15 LeuPro Cys Leu Ser Thr Glu Ala Asp Lys Ser Thr Val Ile Glu 20 25 30 Asn ProGly Ala Leu Cys Ser Pro Gln Ser Gln Arg His Gly His 35 40 45 Tyr Phe ValAla Leu Phe Asp Tyr Gln Ala Arg Thr Ala Glu Asp 50 55 60 Leu Ser Phe ArgAla Gly Asp Lys Leu Gln Val Leu Asp Thr Leu 65 70 75 His Glu Gly Trp TrpPhe Ala Arg His Leu Glu Lys Arg Arg Asp 80 85 90 Gly Ser Ser Gln Gln LeuGln Gly Tyr Ile Pro Ser Asn Tyr Val 95 100 105 Ala Glu Asp Arg Ser LeuGln Ala Glu Pro Trp Phe Phe Gly Ala 110 115 120 Ile Gly Arg Ser Asp AlaGlu Lys Gln Leu Leu Tyr Ser Glu Asn 125 130 135 Lys Thr Gly Ser Phe LeuIle Arg Glu Ser Glu Ser Gln Lys Gly 140 145 150 Glu Phe Ser Leu Ser ValLeu Asp Gly Ala Val Val Lys His Tyr 155 160 165 Arg Ile Lys Arg Leu AspGlu Gly Gly Phe Phe Leu Thr Arg Arg 170 175 180 Arg Ile Phe Ser Thr LeuAsn Glu Phe Val Ser His Tyr Thr Lys 185 190 195 Thr Ser Asp Gly Leu CysVal Lys Leu Gly Lys Pro Cys Leu Lys 200 205 210 Ile Gln Val Pro Ala ProPhe Asp Leu Ser Tyr Lys Thr Val Asp 215 220 225 Gln Trp Glu Ile Asp ArgAsn Ser Ile Gln Leu Leu Lys Arg Leu 230 235 240 Gly Ser Gly Gln Phe GlyGlu Val Trp Glu Gly Leu Trp Asn Asn 245 250 255 Thr Thr Pro Val Ala ValLys Thr Leu Lys Pro Gly Ser Met Asp 260 265 270 Pro Asn Asp Phe Leu ArgGlu Ala Gln Ile Met Lys Asn Leu Arg 275 280 285 His Pro Lys Leu Ile GlnLeu Tyr Ala Val Cys Thr Leu Glu Asp 290 295 300 Pro Ile Tyr Ile Ile ThrGlu Leu Met Arg His Gly Ser Leu Gln 305 310 315 Glu Tyr Leu Gln Asn AspThr Gly Ser Lys Ile His Leu Thr Gln 320 325 330 Gln Val Asp Met Ala AlaGln Val Ala Ser Gly Met Ala Tyr Leu 335 340 345 Glu Ser Arg Asn Tyr IleHis Arg Asp Leu Ala Ala Arg Asn Val 350 355 360 Leu Val Gly Glu His AsnIle Tyr Lys Val Ala Asp Phe Gly Leu 365 370 375 Ala Arg Val Phe Lys ValAsp Asn Glu Asp Ile Tyr Glu Ser Arg 380 385 390 His Glu Ile Lys Leu ProVal Lys Trp Thr Ala Pro Glu Ala Ile 395 400 405 Arg Ser Asn Lys Phe SerIle Lys Ser Asp Val Trp Ser Phe Gly 410 415 420 Ile Leu Leu Tyr Glu IleIle Thr Tyr Gly Lys Met Pro Tyr Ser 425 430 435 Gly Met Thr Gly Ala GlnVal Ile Gln Met Leu Ala Gln Asn Tyr 440 445 450 Arg Leu Pro Gln Pro SerAsn Cys Pro Gln Gln Phe Tyr Asn Ile 455 460 465 Met Leu Glu Cys Trp AsnAla Glu Pro Lys Glu Arg Pro Thr Phe 470 475 480 Glu Thr Leu Arg Trp LysLeu Glu Asp Tyr Phe Glu Thr Asp Ser 485 490 495 Ser Tyr Ser Asp Ala AsnAsn Phe Ile Arg 500 505 404 base pairs Nucleic Acid Single Linear notprovided 21 GCGGCCGCAG AGAAAGCAGA GGATGGGGCT TAGCAGCTGG CAGAGCCAGG 50AGCGGGGAGG TAGCAGAAAG ACCACAAGTA CAAAGAAGTC CTGAAACTTT 100 GGTTTTGCTGCTGCAGCCCA TTGAGAGTGA CGACATGGAG CACAAGACCC 150 TGAAGATCAC CGACTTTGGCCTGGCCCGAG AGTGGCACAA AACCACACAA 200 ATGAGTGCCG CNGGCACCTA CNCCTGGATGGCTCCTGAGG TTATCAAGGC 250 CTCCACCTTC TCTAAGGGCA GTGACGTCTG GAGTTTTGGGGTGCTGCTGT 300 GGGAACTGCT GACCGGGGAG NTGCCATACC GTGGCATTGA CTGCCTTGCT350 GTGGCCTATG GCGTAGCTGT TAACAAGCTC ACACTGCCAT CCATCCACCT 400 GGCC 4043120 base pairs Nucleic Acid Single Linear not provided 22 ATGAGAGCGTTGGCGCGCGA CGGCGGCCAG CTGCCGCTGC TCGTTGTTTT 50 TTCTGCAATG ATATTTGGGACTATTACAAA TCAAGATCTG CCTGTGATCA 100 AGTGTGTTTT AATCAATCAT AAGAACAATGATTCATCAGT GGGGAAGTCA 150 TCATCATATC CCATGGTATC AGAATCCCCG GAAGACCTCGGGTGTGCGTT 200 GAGACCCCAG AGCTCAGGGA CAGTGTACGA AGCTGCCGCT GTGGAAGTGG250 ATGTATCTGC TTCCATCACA CTGCAAGTGC TGGTCGATGC CCCAGGGAAC 300ATTTCCTGTC TCTGGGTCTT TAAGCACAGC TCCCTGAATT GCCAGCCACA 350 TTTTGATTTACAAAACAGAG GAGTTGTTTC CATGGTCATT TTGAAAATGA 400 CAGAAACCCA AGCTGGAGAATACCTACTTT TTATTCAGAG TGAAGCTACC 450 AATTACACAA TATTGTTTAC AGTGAGTATAAGAAATACCC TGCTTTACAC 500 ATTAAGAAGA CCTTACTTTA GAAAAATGGA AAACCAGGACGCCCTGGTCT 550 GCATATCTGA GAGCGTTCCA GAGCGGATCC TGGAATGGGT GCTTTGCGAT600 TCACAGGGGG AAAGCTGTAA AGAAGAAAGT CCAGCTGTTG TTAAAAAGGA 650GGAAAAAGTG CTTCATGAAT TATTTGGGAC GGACATAAGG TGCTGTGCCA 700 GAAATGAACTGGGCAGGGAA TGCACCAGGC TGTTCACAAT AGATCTAAAT 750 CAAACTCCTC AGACCACATTGCCACAATTA TTTCTTAAAG TAGGGGAACC 800 CTTATGGATA AGGTGCAAAG CTGTTCATGTGAACCATGGA TTCGGGCTCA 850 CCTGGGAATT AGAAAACAAA GCACTCGAGG AGGGCAACTACTTTGAGATG 900 AGTACCTATT CAACAAACAG AACTATGATA CGGATTCTGT TTGCTTTTGT950 ATCATCAGTG GCAAGAAACG ACACCGGATA CTACACTTGT TCCTCTTCAA 1000AGCATCCCAG TCAATCAGCT TTGGTTACCA TCGTAGAAAA GGGATTTATA 1050 AATGCTACCAATTCAAGTGA AGATTATGAA ATTGACCAAT ATGAAGAGTT 1100 TTGTTTTTCT GTCAGGTTTAAAGCCTACCC ACAAATCAGA TGTACGTGGA 1150 CCTTCTCTCG AAAATCATTT CCTTGTGAGCAAAAGGGTCT TGATAACGGA 1200 TACAGCATAT CCAAGTTTTG CAATCATAAG CACCAGCCAGGAGAATATAT 1250 ATTCCATGCA GAAAATGATG ATGCCCAATT TACCAAAATG TTCACGCTGT1300 ATATAAGAAG GAAACCTCAA GTCCTCGCAG AAGCTTCGGC AAGTCAGGCG 1350TCCTGTTTCT CGGATGGATA CCCATTACCA TCTTGGACCT GGAAGAAGTG 1400 TTCAGACAAGTCTCCCAACT GCACAGAAGA GATCACAGAA GGAGTCTGGA 1450 ATAGAAAGGC TAACAGAAAAGTGTTTGGAC AGTGGGTGTC GAGCAGTACT 1500 CTAAACATGA GTGAAGCCAT AAAAGGGTTCCTGGTCAAGT GCTGTGCATA 1550 CAATTCCCTT GGCACATCTT GTGAGACGAT CCTTTTAAACTCTCCAGGCC 1600 CCTTCCCTTT CATCCAAGAC AACATCTCAT TCTATGCAAC AATTGGTGTT1650 TGTCTCCTCT TCATTGTCGT TTTAACCCTG CTAATTTGTC ACAAGTACAA 1700AAAGCAATTT AGGTATGAAA GCCAGCTACA GATGGTACAG GTGACCGGAT 1750 CCTCAGATTATGAGTACTTC TACGTTGATT TCAGAGAATA TGAATATGAT 1800 GTCAAATGGG AGTTTCCAAGAGAAAATTTA GAGTTTGGGA AGGTACTAGG 1850 ATCAGGTGCT TTTGGAAAAG TGATGAACGCAACAGCTTAT GGAATTAGCA 1900 AAACAGGAGT CTCAATCCAG GTTACCGTCA AAATGCTGAAAGAAAAAGCA 1950 GACAGCTCTG AAAGAGAGGC ACTCATGTCA GAACTCAAGA TGATGACCCA2000 GCTGGGAAGC CACGAGAATA TTGTGAACCT GCTGGGGGCG TGCACACTGT 2050CAGGACCAAT TTACTTGATT TTTGAATACT GTTGCTATGG TGATCTTCTC 2100 AACTATCTAAGAAGTAAAAG AGAAAAATTT CACAGGACTT GGACAGAGAT 2150 TTTCAAGGAA CACAATTTCAGTTTTTACCC CACTTTCCAA TCACATCCAA 2200 ATTCCAGCAT GCCTGGTTCA AGAGAAGTTCAGATACACCC GGACTCGGAT 2250 CAAATCTCAG GGCTTCATGG GAATTCATTT CACTCTGAAGATGAAATTGA 2300 ATATGAAAAC CAAAAAAGGC TGGAAGAAGA GGAGGACTTG AATGTGCTTA2350 CATTTGAAGA TCTTCTTTGC TTTGCATATC AAGTTGCCAA AGGAATGGAA 2400TTTCTGGAAT TTAAGTCGTG TGTTCACAGA GACCTGGCCG CCAGGAACGT 2450 GCTTGTCACCCACGGGAAAG TGGTGAAGAT ATGTGACTTT GGATTGGCTC 2500 GAGATATCAT GAGTGATTCCAACTATGTTG TCAGGGGCAA TGCCCGTCTG 2550 CCTGTAAAAT GGATGGCCCC CGAAAGCCTGTTTGAAGGCA TCTACACCAT 2600 TAAGAGTGAT GTCTGGTCAT ATGGAATATT ACTGTGGGAAATCTTCTCAC 2650 TTGGTGTGAA TCCTTACCCT GGCATTCCGG TTGATGCTAA CTTCTACAAA2700 CTGATTCAAA ATGGATTTAA AATGGATCAG CCATTTTATG CTACAGAAGA 2750AATATACATT ATAATGCAAT CCTGCTGGGC TTTTGACTCA AGGAAACGGC 2800 CATCCTTCCCTAATTTGACT TCGTTTTTAG GATGTCAGCT GGCAGATGCA 2850 GAAGAAGCGA TGTATCAGAATGTGGATGGC CGTGTTTCGG AATGTCCTCA 2900 CACCTACCAA AACAGGCGAC CTTTCAGCAGAGAGATGGAT TTGGGGCTAC 2950 TCTCTCCGCA GGCTCAGGTC GAAGATTCGT AGAGGAACAATTTAGTTTTA 3000 AGGACTTCAT CCCTCCACCT ATCCCTAACA GGCTGTAGAT TACCAAAACA3050 AGGTTAATTT CATCACTAAA AGAAAATCTA TTATCAACTG CTGCTTCACC 3100AGACTTTTCT CTAGAGAGCG 3120 3969 base pairs Nucleic Acid Single Linearnot provided 23 TCGGCGTCCA CCCGCCCAGG GAGAGTCAGA CCTGGGGGGG CGAGGGCCCC50 CCAAACTCAG TTCGGATCCT ACCCGAGTGA GGCGGCGCCA TGGAGCTCCG 100 GGTGCTGCTCTGCTGGGCTT CGTTGGCCGC AGCTTTGGAA GAGACCCTGC 150 TGAACACAAA ATTGGAAACTGCTGATCTGA AGTGGGTGAC ATTCCCTCAG 200 GTGGACGGGC AGTGGGAGGA ACTGAGCGGCCTGGATGAGG AACAGCACAG 250 CGTGCGCACC TACGAAGTGT GTGACGTGCA GCGTGCCCCGGGCCAGGCCC 300 ACTGGCTTCG CACAGGTTGG GTCCCACGGC GGGGCGCCGT CCACGTGTAC350 GCCACGCTGC GCTTCACCAT GCTCGAGTGC CTGTCCCTGC CTCGGGCTGG 400GCGCTCCTGC AAGGAGACCT TCACCGTCTT CTACTATGAG AGCGATGCGG 450 ACACGGCCACGGCCCTCACG CCAGCCTGGA TGGAGAACCC CTACATCAAG 500 GTGGACACGG TGGCCGCGGAGCATCTCACC CGGAAGCGCC CTGGGGCCGA 550 GGCCACCGGG AAGGTGAATG TCAAGACGCTGCGTCTGGGA CCGCTCAGCA 600 AGGCTGGCTT CTACCTGGCC TTCCAGGACC AGGGTGCCTGCATGGCCCTG 650 CTATCCCTGC ACCTCTTCTA CAAAAAGTGC GCCCAGCTGA CTGTGAACCT700 GACTCGATTC CCGGAGACTG TGCCTCGGGA GCTGGTTGTG CCCGTGGCCG 750GTAGCTGCGT GGTGGATGCC GTCCCCGCCC CTGGCCCCAG CCCCAGCCTC 800 TACTGCCGTGAGGATGGCCA GTGGGCCGAA CAGCCGGTCA CGGGCTGCAG 850 CTGTGCTCCG GGGTTCGAGGCAGCTGAGGG GAACACCAAG TGCCGAGCCT 900 GTGCCCAGGG CACCTTCAAG CCCCTGTCAGGAGAAGGGTC CTGCCAGCCA 950 TGCCCAGCCA ATAGCCACTC TAACACCATT GGATCAGCCGTCTGCCAGTG 1000 CCGCGTCGGG TACTTCCGGG CACGCACAGA CCCCCGGGGT GCACCCTGCA1050 CCACCCCTCC TTCGGCTCCG CGGAGCGTGG TTTCCCGCCT GAACGGCTCC 1100TCCCTGCACC TGGAATGGAG TGCCCCCCTG GAGTCTGGTG GCCGAGAGGA 1150 CCTCACCTACGCCCTCCGCT GCCGGGAGTG CCGACCCGGA GGCTCCTGTG 1200 CGCCCTGCGG GGGAGACCTGACTTTTGACC CCGGCCCCCG GGACCTGGTG 1250 GAGCCCTGGG TGGTGGTTCG AGGGCTACGTCCTGACTTCA CCTATACCTT 1300 TGAGGTCACT GCATTGAACG GGGTATCCTC CTTAGCCACGGGGCCCGTCC 1350 CATTTGAGCC TGTCAATGTC ACCACTGACC GAGAGGTACC TCCTGCAGTG1400 TCTGACATCC GGGTGACGCG GTCCTCACCC AGCAGCTTGA GCCTGGCCTG 1450GGCTGTTCCC CGGGCACCCA GTGGGGCTGT GCTGGACTAC GAGGTCAAAT 1500 ACCATGAGAAGGGCGCCGAG GGTCCCAGCA GCGTGCGGTT CCTGAAGACG 1550 TCAGAAAACC GGGCAGAGCTGCGGGGGCTG AAGCGGGGAG CCAGCTACCT 1600 GGTGCAGGTA CGGGCGCGCT CTGAGGCCGGCTACGGGCCC TTCGGCCAGG 1650 AACATCACAG CCAGACCCAA CTGGATGAGA GCGAGGGCTGGCGGGAGCAG 1700 CTGGCCCTGA TTGCGGGCAC GGCAGTCGTG GGTGTGGTCC TGGTCCTGGT1750 GGTCATTGTG GTCGCAGTTC TCTGCCTCAG GAAGCAGAGC AATGGGAGAG 1800AAGCAGAATA TTCGGACAAA CACGGACAGT ATCTCATCGG ACATGGTACT 1850 AAGGTCTACATCGACCCCTT CACTTATGAA GACCCTAATG AGGCTGTGAG 1900 GGAATTTGCA AAAGAGATCGATGTCTCCTA CGTCAAGATT GAAGAGGTGA 1950 TTGGTGCAGG TGAGTTTGGC GAGGTGTGCCGGGGGCGGCT CAAGGCCCCA 2000 GGGAAGAAGG AGAGCTGTGT GGCAATCAAG ACCCTGAAGGGTGGCTACAC 2050 GGAGCGGCAG CGGCGTGAGT TTCTGAGCGA GGCCTCCATC ATGGGCCAGT2100 TCGAGCACCC CAATATCATC CGCCTGGAGG GCGTGGTCAC CAACAGCATG 2150CCCGTCATGA TTCTCACAGA GTTCATGGAG AACGGCGCCC TGGACTCCTT 2200 CCTGCGGCTAAACGACGGAC AGTTCACAGT CATCCAGCTC GTGGGCATGC 2250 TGCGGGGCAT CGCCTCGGGCATGCGGTACC TTGCCGAGAT GAGCTACGTC 2300 CACCGAGACC TGGCTGCTCG CAACATCCTAGTCAACAGCA ACCTCGTCTG 2350 CAAAGTGTCT GACTTTGGCC TTTCCCGATT CCTGGAGGAGAACTCTTCCG 2400 ATCCCACCTA CACGAGCTCC CTGGGAGGAA AGATTCCCAT CCGATGGACT2450 GCCCCGGAGG CCATTGCCTT CCGGAAGTTC ACTTCCGCCA GTGATGCCTG 2500GAGTTACGGG ATTGTGATGT GGGAGGTGAT GTCATTTGGG GAGAGGCCGT 2550 ACTGGGACATGAGCAATCAG GACGTGATCA ATGCCATTGA ACAGGACTAC 2600 CGGCTGCCCC CGCCCCCAGACTGTCCCACC TCCCTCCACC AGCTCATGCT 2650 GGACTGTTGG CAGAAAGACC GGAATGCCCGGCCCCGCTTC CCCCAGGTGG 2700 TCAGCGCCCT GGACAAGATG ATCCGGAACC CCGCCAGCCTCAAAATCGTG 2750 GCCCGGGAGA ATGGCGGGGC CTCACACCCT CTCCTGGACC AGCGGCAGCC2800 TCACTACTCA GCTTTTGGCT CTGTGGGCGA GTGGCTTCGG GCCATCAAAA 2850TGGGAAGATA CGAAGAAAGT TTCGCAGCCG CTGGCTTTGG CTCCTTCGAG 2900 CTGGTCAGCCAGATCTCTGC TGAGGACCTG CTCCGAATCG GAGTCACTCT 2950 GGCGGGACAC CAGAAGAAAATCTTGGCCAG TGTCCAGCAC ATGAAGTCCC 3000 AGGCCAAGCC GGGAACCCCG GGTGGGACAGGAGGACCGGC CCCGCAGTAC 3050 TGACCTGCAG GAACTCCCCA CCCCAGGGAC ACCGCCTCCCCATTTTCCGG 3100 GGCAGAGTGG GGACTCACAG AGGCCCCCAG CCCTGTGCCC CGCTGGATTG3150 CACTTTGAGC CCGTGGGGTG AGGAGTTGGC AATTTGGAGA GACAGGATTT 3200GGGGGTTCTG CCATAATAGG AGGGGAAAAT CACCCCCCAG CCACCTCGGG 3250 GAACTCCAGACCAAGGGTGA GGGCGCCTTT CCCTCAGGAC TGGGTGTGAC 3300 CAGAGGAAAA GGAAGTGCCCAACATCTCCC AGCCTCCCCA GGTGCCCCCC 3350 TCACCTTGAT GGGTGCGTTC CCGCAGACCAAAGAGAGTGT GACTCCCTTG 3400 CCAGCTCCAG AGTGGGGGGG CTGTCCCAGG GGGCAAGAAGGGGTGTCAGG 3450 GCCCAGTGAC AAAATCATTG GGGTTTGTAG TCCCAACTTG CTGCTGTCAC3500 CACCAAACTC AATCATTTTT TTCCCTTGTA AATGCCCCTC CCCCAGCTGC 3550TGCCTTCATA TTGAAGGTTT TTGAGTTTTG TTTTTGGTCT TAATTTTTCT 3600 CCCCGTTCCCTTTTTGTTTC TTCGTTTTGT TTTTCTACCG TCCTTGTCAT 3650 AACTTTGTGT TGGAGGGAACCTGTTTCACT ATGGCCTCCT TTGCCCAAGT 3700 TGAAACAGGG GCCCATCATC ATGTCTGTTTCCAGAACAGT GCCTTGGTCA 3750 TCCCACATCC CCGGACCCCG CCTGGGACCC CCAAGCTGTGTCCTATGAAG 3800 GGGTGTGGGG TGAGGTAGTG AAAAGGGCGG TAGTTGGTGG TGGAACCCAG3850 AAACGGACGC CGGTGCTTGG AGGGGTTCTT AAATTATATT TAAAAAAGTA 3900ACTTTTTGTA TAAATAAAAG AAAATGGGAC GTGTCCCAGC TCCAGGGGTA 3950 AAAAAAAAAAAAAAAAAAA 3969 1276 amino acids Amino Acid Linear not provided 24 MetGlu Leu Arg Val Leu Leu Cys Trp Ala Ser Leu Ala Ala Ala 1 5 10 15 LeuGlu Glu Thr Leu Leu Asn Thr Lys Leu Glu Thr Ala Asp Leu 20 25 30 Lys TrpVal Thr Phe Pro Gln Val Asp Gly Gln Trp Glu Glu Leu 35 40 45 Ser Gly LeuAsp Glu Glu Gln His Ser Val Arg Thr Tyr Glu Val 50 55 60 Cys Asp Val GlnArg Ala Pro Gly Gln Ala His Trp Leu Arg Thr 65 70 75 Gly Trp Val Pro ArgArg Gly Ala Val His Val Tyr Ala Thr Leu 80 85 90 Arg Phe Thr Met Leu GluCys Leu Ser Leu Pro Arg Ala Gly Arg 95 100 105 Ser Cys Lys Glu Thr PheThr Val Phe Tyr Tyr Glu Ser Asp Ala 110 115 120 Asp Thr Ala Thr Ala LeuThr Pro Ala Trp Met Glu Asn Pro Tyr 125 130 135 Ile Lys Val Asp Thr ValAla Ala Glu His Leu Thr Arg Lys Arg 140 145 150 Pro Gly Ala Glu Ala ThrGly Lys Val Asn Val Lys Thr Leu Arg 155 160 165 Leu Gly Pro Leu Ser LysAla Gly Phe Tyr Leu Ala Phe Gln Asp 170 175 180 Gln Gly Ala Cys Met AlaLeu Leu Ser Leu His Leu Phe Tyr Lys 185 190 195 Lys Cys Ala Gln Leu ThrVal Asn Leu Thr Arg Phe Pro Glu Thr 200 205 210 Val Pro Arg Glu Leu ValVal Pro Val Ala Gly Ser Cys Val Val 215 220 225 Asp Ala Val Pro Ala ProGly Pro Ser Pro Ser Leu Tyr Cys Arg 230 235 240 Glu Asp Gly Gln Trp AlaGlu Gln Pro Val Thr Gly Cys Ser Cys 245 250 255 Ala Pro Gly Phe Glu AlaAla Glu Gly Asn Thr Lys Cys Arg Ala 260 265 270 Cys Ala Gln Gly Thr PheLys Pro Leu Ser Gly Glu Gly Ser Cys 275 280 285 Gln Pro Cys Pro Ala AsnSer His Ser Asn Thr Ile Gly Ser Ala 290 295 300 Val Cys Gln Cys Arg ValGly Tyr Phe Arg Ala Arg Thr Asp Pro 305 310 315 Arg Gly Ala Pro Cys ThrThr Pro Pro Ser Ala Pro Arg Ser Val 320 325 330 Val Ser Arg Leu Asn GlySer Ser Leu His Leu Glu Trp Ser Ala 335 340 345 Pro Leu Glu Ser Gly GlyArg Glu Asp Leu Thr Tyr Ala Leu Arg 350 355 360 Cys Arg Glu Cys Arg ProGly Gly Ser Cys Ala Pro Cys Gly Gly 365 370 375 Asp Leu Thr Phe Asp ProGly Pro Arg Asp Leu Val Glu Pro Trp 380 385 390 Val Val Val Arg Gly LeuArg Pro Asp Phe Thr Tyr Thr Phe Glu 395 400 405 Val Thr Ala Leu Asn GlyVal Ser Ser Leu Ala Thr Gly Pro Val 410 415 420 Pro Phe Glu Pro Val AsnVal Thr Thr Asp Arg Glu Val Pro Pro 425 430 435 Ala Val Ser Asp Ile ArgVal Thr Arg Ser Ser Pro Ser Ser Leu 440 445 450 Ser Leu Ala Trp Ala ValPro Arg Ala Pro Ser Gly Ala Val Leu 455 460 465 Asp Tyr Glu Val Lys TyrHis Glu Lys Gly Ala Glu Gly Pro Ser 470 475 480 Ser Val Arg Phe Leu LysThr Ser Glu Asn Arg Ala Glu Leu Arg 485 490 495 Gly Leu Lys Arg Gly AlaSer Tyr Leu Val Gln Val Arg Ala Arg 500 505 510 Ser Glu Ala Gly Tyr GlyPro Phe Gly Gln Glu His His Ser Gln 515 520 525 Thr Gln Leu Asp Glu SerGlu Gly Trp Arg Glu Gln Leu Ala Leu 530 535 540 Ile Ala Gly Thr Ala ValVal Gly Val Val Leu Val Leu Val Val 545 550 555 Ile Val Val Ala Val LeuCys Leu Arg Lys Gln Ser Asn Gly Arg 560 565 570 Glu Ala Glu Tyr Ser AspLys His Gly Gln Tyr Leu Ile Gly His 575 580 585 Gly Thr Lys Val Tyr IleAsp Pro Phe Thr Tyr Glu Asp Pro Asn 590 595 600 Glu Ala Val Arg Glu PheAla Lys Glu Ile Asp Val Ser Tyr Val 605 610 615 Lys Ile Glu Glu Val IleGly Ala Gly Glu Phe Gly Glu Val Cys 620 625 630 Arg Gly Arg Leu Lys AlaPro Gly Lys Lys Glu Ser Cys Val Ala 635 640 645 Ile Lys Thr Leu Lys GlyGly Tyr Thr Glu Arg Gln Arg Arg Glu 650 655 660 Phe Leu Ser Glu Ala SerIle Met Gly Gln Phe Glu His Pro Asn 665 670 675 Ile Ile Arg Leu Glu GlyVal Val Thr Asn Ser Met Pro Val Met 680 685 690 Ile Leu Thr Glu Phe MetGlu Asn Gly Ala Leu Asp Ser Phe Leu 695 700 705 Arg Leu Asn Asp Gly GlnPhe Thr Val Ile Gln Leu Val Gly Met 710 715 720 Leu Arg Gly Ile Ala SerGly Met Arg Tyr Leu Ala Glu Met Ser 725 730 735 Tyr Val His Arg Asp LeuAla Ala Arg Asn Ile Leu Val Asn Ser 740 745 750 Asn Leu Val Cys Lys ValSer Asp Phe Gly Leu Ser Arg Phe Leu 755 760 765 Glu Glu Asn Ser Ser AspPro Thr Tyr Thr Ser Ser Leu Gly Gly 770 775 780 Lys Ile Pro Ile Arg TrpThr Ala Pro Glu Ala Ile Ala Phe Arg 785 790 795 Lys Phe Thr Ser Ala SerAsp Ala Trp Ser Tyr Gly Ile Val Met 800 805 810 Trp Glu Val Met Ser PheGly Glu Arg Pro Tyr Trp Asp Met Ser 815 820 825 Asn Gln Asp Val Ile AsnAla Ile Glu Gln Asp Tyr Arg Leu Pro 830 835 840 Pro Pro Pro Asp Cys ProThr Ser Leu His Gln Leu Met Leu Asp 845 850 855 Cys Trp Gln Lys Asp ArgAsn Ala Arg Pro Arg Phe Pro Gln Val 860 865 870 Val Ser Ala Leu Asp LysMet Ile Arg Asn Pro Ala Ser Leu Lys 875 880 885 Ile Val Ala Arg Glu AsnGly Gly Ala Ser His Pro Leu Leu Asp 890 895 900 Gln Arg Gln Pro His TyrSer Ala Phe Gly Ser Val Gly Glu Trp 905 910 915 Leu Arg Ala Ile Lys MetGly Arg Tyr Glu Glu Ser Phe Ala Ala 920 925 930 Ala Gly Phe Gly Ser PheGlu Leu Val Ser Gln Ile Ser Ala Glu 935 940 945 Asp Leu Leu Arg Ile GlyVal Thr Leu Ala Gly His Gln Lys Lys 950 955 960 Ile Leu Ala Ser Val GlnHis Met Lys Ser Gln Ala Lys Pro Gly 965 970 975 Thr Pro Gly Gly Thr GlyGly Pro Ala Pro Gln Tyr Pro Ala Gly 980 985 990 Thr Pro His Pro Arg AspThr Ala Ser Pro Phe Ser Gly Ala Glu 995 1000 1005 Trp Gly Leu Thr GluAla Pro Ser Pro Val Pro Arg Trp Ile Ala 1010 1015 1020 Leu Ala Arg GlyVal Arg Ser Trp Gln Phe Gly Glu Thr Gly Phe 1025 1030 1035 Gly Gly SerAla Ile Ile Gly Gly Glu Asn His Pro Pro Ala Thr 1040 1045 1050 Ser GlyAsn Ser Arg Pro Arg Val Arg Ala Pro Phe Pro Gln Asp 1055 1060 1065 TrpVal Pro Glu Glu Lys Glu Val Pro Asn Ile Ser Gln Pro Pro 1070 1075 1080Gln Val Pro Pro Ser Pro Trp Val Arg Ser Arg Arg Pro Lys Arg 1085 10901095 Val Leu Pro Cys Gln Leu Gln Ser Gly Gly Ala Val Pro Gly Gly 11001105 1110 Lys Lys Gly Cys Gln Gly Pro Val Thr Lys Ser Leu Gly Phe Val1115 1120 1125 Val Pro Thr Cys Cys Cys His His Gln Thr Gln Ser Phe PheSer 1130 1135 1140 Leu Val Asn Ala Pro Pro Pro Ala Ala Ala Phe Ile LeuLys Val 1145 1150 1155 Phe Glu Phe Cys Phe Trp Ser Phe Phe Ser Pro PhePro Phe Cys 1160 1165 1170 Phe Phe Val Leu Phe Phe Tyr Arg Pro Cys HisAsn Phe Val Leu 1175 1180 1185 Glu Gly Thr Cys Phe Thr Met Ala Ser PheAla Gln Val Glu Thr 1190 1195 1200 Gly Ala His His His Val Cys Phe GlnAsn Ser Ala Leu Val Ile 1205 1210 1215 Pro His Pro Arg Thr Pro Pro GlyThr Pro Lys Leu Cys Pro Met 1220 1225 1230 Lys Gly Cys Gly Val Arg LysGly Arg Leu Val Val Glu Pro Arg 1235 1240 1245 Asn Gly Arg Arg Cys LeuGlu Gly Phe Leu Asn Tyr Ile Lys Ser 1250 1255 1260 Asn Phe Leu Tyr LysLys Lys Met Gly Arg Val Pro Ala Pro Gly 1265 1270 1275 Val 1276 59 aminoacids Amino Acid Linear not provided 25 Ala Arg Asn Ile Leu Val Asn SerAsn Leu Val Cys Lys Val Ser 1 5 10 15 Asp Phe Gly Leu Ser Arg Phe LeuGlu Asp Asp Thr Ser Asp Pro 20 25 30 Thr Tyr Thr Ser Ala Leu Gly Gly LysIle Pro Met Arg Trp Thr 35 40 45 Ala Pro Glu Ala Ile Gln Tyr Arg Lys PheAla Ser Ala Ser 50 55 59 54 amino acids Amino Acid Linear not provided26 Asn Val Leu Val Lys Ser Pro Asn His Val Lys Ile Thr Asp Phe 1 5 10 15Gly Leu Ala Arg Leu Leu Glu Gly Asp Glu Lys Glu Tyr Asn Ala 20 25 30 AspGly Gly Lys Met Pro Ile Lys Trp Met Ala Leu Glu Cys Ile 35 40 45 His TyrArg Lys Phe Thr His Gln Ser 50 54 54 amino acids Amino Acid Linear notprovided 27 Asn Cys Met Leu Ala Gly Asp Met Thr Val Cys Val Ala Asp Phe1 5 10 15 Gly Leu Ser Trp Lys Ile Tyr Ser Gly Ala Thr Ile Val Arg Gly 2025 30 Cys Ala Ser Lys Leu Pro Val Lys Trp Leu Ala Leu Gly Ser Leu 35 4045 Ala Asp Asn Leu Tyr Thr Val His Ser 50 54 27 amino acids Amino AcidLinear not provided 28 Asn Cys Leu Val Gly Lys Asn Tyr Thr Ile Lys IleAla Asp Phe 1 5 10 15 Gly Met Ser Arg Asn Leu Tyr Ser Gly Asp Tyr Tyr 2025 27 58 amino acids Amino Acid Linear not provided 29 Thr Arg Asn IleLeu Val Glu Asn Glu Asn Arg Val Lys Ile Gly 1 5 10 15 Asp Phe Gly LeuThr Lys Val Leu Pro Gln Asp Lys Glu Tyr Tyr 20 25 30 Lys Val Lys Glu ProGly Glu Ser Pro Ile Phe Trp Tyr Ala Pro 35 40 45 Glu Ser Leu Thr Glu SerLeu Phe Ser Val Ala Ser Asp 50 55 58 58 amino acids Amino Acid Linearnot provided 30 Ala Arg Asn Ile Leu Val Asn Ser Asn Leu Val Cys Lys ValSer 1 5 10 15 Asp Phe Gly Met Ser Arg Val Leu Glu Asp Asp Pro Glu AlaAla 20 25 30 Tyr Thr Thr Arg Gly Gly Lys Ile Pro Ile Arg Trp Thr Ala Pro35 40 45 Glu Ala Ile Ala Tyr Arg Lys Phe Thr Ser Ala Ser Asp 50 55 584425 base pairs Nucleic Acid Single Linear not provided 31 TCGGGTCGGACCCACGCGCA GCGGCCGGAG ATGCAGCGGG GCGCCGCGCT 50 GTGCCTGCGA CTGTGGCTCTGCCTGGGACT CCTGGACGGC CTGGTGAGTG 100 GCTACTCCAT GACCCCCCCG ACCTTGAACATCACGGAGGA GTCACACGTC 150 ATCGACACCG GTGACAGCCT GTCCATCTCC TGCAGGGGACAGCACCCCCT 200 CGAGTGGGCT TGGCCAGGAG CTCAGGAGGC GCCAGCCACC GGAGACAAGG250 ACAGCGAGGA CACGGGGGTG GTGCGAGACT GCGAGGGCAC AGACGCCAGG 300CCCTACTGCA AGGTGTTGCT GCTGCACGAG GTACATGCCA ACGACACAGG 350 CAGCTACGTCTGCTACTACA AGTACATCAA GGCACGCATC GAGGGCACCA 400 CGGCCGCCAG CTCCTACGTGTTCGTGAGAG ACTTTGAGCA GCCATTCATC 450 AACAAGCCTG ACACGCTCTT GGTCAACAGGAAGGACGCCA TGTGGGTGCC 500 CTGTCTGGTG TCCATCCCCG GCCTCAATGT CACGCTGCGCTCGCAAAGCT 550 CGGTGCTGTG GCCAGACGGG CAGGAGGTGG TGTGGGATGA CCGGCGGGGC600 ATGCTCGTGT CCACGCCACT GCTGCACGAT GCCCTGTACC TGCAGTGCGA 650GACCACCTGG GGAGACCAGG ACTTCCTTTC CAACCCCTTC CTGGTGCACA 700 TCACAGGCAACGAGCTCTAT GACATCCAGC TGTTGCCCAG GAAGTCGCTG 750 GAGCTGCTGG TAGGGGAGAAGCTGGTCCTG AACTGCACCG TGTGGGCTGA 800 GTTTAACTCA GGTGTCACCT TTGACTGGGACTACCCAGGG AAGCAGGCAG 850 AGCGGGGTAA GTGGGTGCCC GAGCGACGCT CCCAGCAGACCCACACAGAA 900 CTCTCCAGCA TCCTGACCAT CCACAACGTC AGCCAGCACG ACCTGGGCTC950 GTATGTGTGC AAGGCCAACA ACGGCATCCA GCGATTTCGG GAGAGCACCG 1000AGGTCATTGT GCATGAAAAT CCCTTCATCA GCGTCGAGTG GCTCAAAGGA 1050 CCCATCCTGGAGGCCACGGC AGGAGACGAG CTGGTGAAGC TGCCCGTGAA 1100 GCTGGCAGCG TACCCCCCGCCCGAGTTCCA GTGGTACAAG GATGGAAAGG 1150 CACTGTCCGG GCGCCACAGT CCACATGCCCTGGTGCTCAA GGAGGTGACA 1200 GAGGCCAGCA CAGGCACCTA CACCCTCGCC CTGTGGAACTCCGCTGCTGG 1250 CCTGAGGCGC AACATCAGCC TGGAGCTGGT GGTGAATGTG CCCCCCCAGA1300 TACATGAGAA GGAGGCCTCC TCCCCCAGCA TCTACTCGCG TCACAGCCGC 1350CAGGCCCTCA CCTGCACGGC CTACGGGGTG CCCCTGCCTC TCAGCATCCA 1400 GTGGCACTGGCGGCCCTGGA CACCCTGCAA GATGTTTGCC CAGCGTAGTC 1450 TCCGGCGGCG GCAGCAGCAAGACCTCATGC CACAGTGCCG TGACTGGAGG 1500 GCGGTGACCA CGCAGGATGC CGTGAACCCCATCGAGAGCC TGGACACCTG 1550 GACCGAGTTT GTGGAGGGAA AGAATAAGAC TGTGAGCAAGCTGGTGATCC 1600 AGAATGCCAA CGTGTCTGCC ATGTACAAGT GTGTGGTCTC CAACAAGGTG1650 GGCCAGGATG AGCGGCTCAT CTACTTCTAT GTGACCACCA TCCCCGACGG 1700CTTCACCATC GAATCCAAGC CATCCGAGGA GCTACTAGAG GGCCAGCCGG 1750 TGCTCCTGAGCTGCCAAGCC GACAGCTACA AGTACGAGCA TCTGCGCTGG 1800 TACCGCCTCA ACCTGTCCACGCTGCACGAT GCGCACGGGA ACCCGCTTCT 1850 GCTCGACTGC AAGAACGTGC ATCTGTTCGCCACCCCTCTG GCCGCCAGCC 1900 TGGAGGAGGT GGCACCTGGG GCGCGCCACG CCACGCTCAGCCTGAGTATC 1950 CCCCGCGTCG CGCCCGAGCA CGAGGGCCAC TATGTGTGCG AAGTGCAAGA2000 CCGGCGCAGC CATGACAAGC ACTGCCACAA GAAGTACCTG TCGGTGCAGG 2050CCCTGGAAGC CCCTCGGCTC ACGCAGAACT TGACCGACCT CCTGGTGAAC 2100 GTGAGCGACTCGCTGGAGAT GCAGTGCTTG GTGGCCGGAG CGCACGCGCC 2150 CAGCATCGTG TGGTACAAAGACGAGAGGCT GCTGGAGGAA AAGTCTGGAG 2200 TCGACTTGGC GGACTCCAAC CAGAAGCTGAGCATCCAGCG CGTGCGCGAG 2250 GAGGATGCGG GACGCTATCT GTGCAGCGTG TGCAACGCCAAGGGCTGCGT 2300 CAACTCCTCC GCCAGCGTGG CCGTGGAAGG CTCCGAGGAT AAGGGCAGCA2350 TGGAGATCGT GATCCTTGTC GGTACCGGCG TCATCGCTGT CTTCTTCTGG 2400GTCCTCCTCC TCCTCATCTT CTGTAACATG AGGAGGCCGG CCCACGCAGA 2450 CATCAAGACGGGCTACCTGT CCATCATCAT GGACCCCGGG GAGGTGCCTC 2500 TGGAGGAGCA ATGCGAATACCTGTCCTACG ATGCCAGCCA GTGGGAATTC 2550 CCCCGAGAGC GGCTGCACCT GGGGAGAGTGCTCGGCTACG GCGCCTTCGG 2600 GAAGGTGGTG GAAGCCTCCG CTTTCGGCAT CCACAAGGGCAGCAGCTGTG 2650 ACACCGTGGC CGTGAAAATG CTGAAAGAGG GCGCCACGGC CAGCGAGCAC2700 CGCGCGCTGA TGTCGGAGCT CAAGATCCTC ATTCACATCG GCAACCACCT 2750CAACGTGGTC AACCTCCTCG GGGCGTGCAC CAAGCCGCAG GGCCCCCTCA 2800 TGGTGATCGTGGAGTTCTGC AAGTACGGCA ACCTCTCCAA CTTCCTGCGC 2850 GCCAAGCGGG ACGCCTTCAGCCCCTGCGCG GAGAAGTCTC CCGAGCAGCG 2900 CGGACGCTTC CGCGCCATGG TGGAGCTCGCCAGGCTGGAT CGGAGGCGGC 2950 CGGGGAGCAG CGACAGGGTC CTCTTCGCGC GGTTCTCGAAGACCGAGGGC 3000 GGAGCGAGGC GGGCTTCTCC AGACCAAGAA GCTGAGGACC TGTGGCTGAG3050 CCCGCTGACC ATGGAAGATC TTGTCTGCTA CAGCTTCCAG GTGGCCAGAG 3100GGATGGAGTT CCTGGCTTCC CGAAAGTGCA TCCACAGAGA CCTGGCTGCT 3150 CGGAACATTCTGCTGTCGGA AAGCGACGTG GTGAAGATCT GTGACTTTGG 3200 CCTTGCCCGG GACATCTACAAAGACCCTGA CTACGTCCGC AAGGGCAGTG 3250 CCCGGCTGCC CCTGAAGTGG ATGGCCCCTGAAAGCATCTT CGACAAGGTG 3300 TACACCACGC AGAGTGACGT GTGGTCCTTT GGGGTGCTTCTCTGGGAGAT 3350 CTTCTCTCTG GGGGCCTCCC CGTACCCTGG GGTGCAGATC AATGAGGAGT3400 TCTGCCAGCG GCTGAGAGAC GGCACAAGGA TGAGGGCCCC GGAGCTGGCC 3450ACTCCCGCCA TACGCCGCAT CATGCTGAAC TGCTGGTCCG GAGACCCCAA 3500 GGCGAGACCTGCATTCTCGG AGCTGGTGGA GATCCTGGGG GACCTGCTCC 3550 AGGGCAGGGG CCTGCAAGAGGAAGAGGAGG TCTGCATGGC CCCGCGCAGC 3600 TCTCAGAGCT CAGAAGAGGG CAGCTTCTCGCAGGTGTCCA CCATGGCCCT 3650 ACACATCGCC CAGGCTGACG CTGAGGACAG CCCGCCAAGCCTGCAGCGCC 3700 ACAGCCTGGC CGCCAGGTAT TACAACTGGG TGTCCTTTCC CGGGTGCCTG3750 GCCAGAGGGG CTGAGACCCG TGGTTCCTCC AGGATGAAGA CATTTGAGGA 3800ATTCCCCATG ACCCCAACGA CCTACAAAGG CTCTGTGGAC AACCAGACAG 3850 ACAGTGGGATGGTGCTGGCC TCGGAGGAGT TTGAGCAGAT AGAGAGCAGG 3900 CATAGACAAG AAAGCGGCTTCAGGTAGCTG AAGCAGAGAG AGAGAAGGCA 3950 GCATACGTCA GCATTTTCTT CTCTGCACTTATAAGAAAGA TCAAAGACTT 4000 TAAGACTTTC GCTATTTCTT CTGCTATCTA CTACAAACTTCAAAGAGGAA 4050 CCAGGAGGCC AAGAGGAGCA TGAAAGTGGA CAAGGAGTGT GACCACTGAA4100 GCACCACAGG GAGGGGTTAG GCCTCCGGAT GACTGCGGGC AGGCCTGGAT 4150AATATCCAGC CTCCCACAAG AAGCTGGTGG AGCAGAGTGT TCCCTGACTC 4200 CTCCAAGGAAAGGGAGACGC CCTTTCATGG TCTGCTGAGT AACAGGTGCC 4250 TTCCCAGACA CTGGCGTTACTGCTTGACCA AAGAGCCCTC AAGCGGCCCT 4300 TATGCCAGCG TGACAGAGGG CTCACCTCTTGCCTTCTAGG TCACTTCTCA 4350 CAATGTCCCT TCAGCACCTG ACCCTGTGCC CGCCAGTTATTCCTTGGTAA 4400 TATGAGTAAT ACATCAAAGA GTAGT 4425 4425 base pairs NucleicAcid Single Linear not provided 32 AGCCCAGCCT GGGTGCGCGT CGCCGGCCTCTACGTCGCCC CGCGGCGCGA 50 CACGGACGCT GACACCGAGA CGGACCCTGA GGACCTGCCGGACCACTCAC 100 CGATGAGGTA CTGGGGGGGC TGGAACTTGT AGTGCCTCCT CAGTGTGCAG150 TAGCTGTGGC CACTGTCGGA CAGGTAGAGG ACGTCCCCTG TCGTGGGGGA 200GCTCACCCGA ACCGGTCCTC GAGTCCTCCG CGGTCGGTGG CCTCTGTTCC 250 TGTCGCTCCTGTGCCCCCAC CACGCTCTGA CGCTCCCGTG TCTGCGGTCC 300 GGGATGACGT TCCACAACGACGACGTGCTC CATGTACGGT TGCTGTGTCC 350 GTCGATGCAG ACGATGATGT TCATGTAGTTCCGTGCGTAG CTCCCGTGGT 400 GCCGGCGGTC GAGGATGCAC AAGCACTCTC TGAAACTCGTCGGTAAGTAG 450 TTGTTCGGAC TGTGCGAGAA CCAGTTGTCC TTCCTGCGGT ACACCCACGG500 GACAGACCAC AGGTAGGGGC CGGAGTTACA GTGCGACGCG AGCGTTTCGA 550GCCACGACAC CGGTCTGCCC GTCCTCCACC ACACCCTACT GGCCGCCCCG 600 TACGAGCACAGGTGCGGTGA CGACGTGCTA CGGGACATGG ACGTCACGCT 650 CTGGTGGACC CCTCTGGTCCTGAAGGAAAG GTTGGGGAAG GACCACGTGT 700 AGTGTCCGTT GCTCGAGATA CTGTAGGTCGACAACGGGTC CTTCAGCGAC 750 CTCGACGACC ATCCCCTCTT CGACCAGGAC TTGACGTGGCACACCCGACT 800 CAAATTGAGT CCACAGTGGA AACTGACCCT GATGGGTCCC TTCGTCCGTC850 TCGCCCCATT CACCCACGGG CTCGCTGCGA GGGTCGTCTG GGTGTGTCTT 900GAGAGGTCGT AGGACTGGTA GGTGTTGCAG TCGGTCGTGC TGGACCCGAG 950 CATACACACGTTCCGGTTGT TGCCGTAGGT CGCTAAAGCC CTCTCGTGGC 1000 TCCAGTAACA CGTACTTTTAGGGAAGTAGT CGCAGCTCAC CGAGTTTCCT 1050 GGGTAGGACC TCCGGTGCCG TCCTCTGCTCGACCACTTCG ACGGGCACTT 1100 CGACCGTCGC ATGGGGGGCG GGCTCAAGGT CACCATGTTCCTACCTTTCC 1150 GTGACAGGCC CGCGGTGTCA GGTGTACGGG ACCACGAGTT CCTCCACTGT1200 CTCCGGTCGT GTCCGTGGAT GTGGGAGCGG GACACCTTGA GGCGACGACC 1250GGACTCCGCG TTGTAGTCGG ACCTCGACCA CCACTTACAC GGGGGGGTCT 1300 ATGTACTCTTCCTCCGGAGG AGGGGGTCGT AGATGAGCGC AGTGTCGGCG 1350 GTCCGGGAGT GGACGTGCCGGATGCCCCAC GGGGACGGAG AGTCGTAGGT 1400 CACCGTGACC GCCGGGACCT GTGGGACGTTCTACAAACGG GTCGCATCAG 1450 AGGCCGCCGC CGTCGTCGTT CTGGAGTACG GTGTCACGGCACTGACCTCC 1500 CGCCACTGGT GCGTCCTACG GCACTTGGGG TAGCTCTCGG ACCTGTGGAC1550 CTGGCTCAAA CACCTCCCTT TCTTATTCTG ACACTCGTTC GACCACTAGG 1600TCTTACGGTT GCACAGACGG TACATGTTCA CACACCAGAG GTTGTTCCAC 1650 CCGGTCCTACTCGCCGAGTA GATGAAGATA CACTGGTGGT AGGGGCTGCC 1700 GAAGTGGTAG CTTAGGTTCGGTAGGCTCCT CGATGATCTC CCGGTCGGCC 1750 ACGAGGACTC GACGGTTCGG CTGTCGATGTTCATGCTCGT AGACGCGACC 1800 ATGGCGGAGT TGGACAGGTG CGACGTGCTA CGCGTGCCCTTGGGCGAAGA 1850 CGAGCTGACG TTCTTGCACG TAGACAAGCG GTGGGGAGAC CGGCGGTCGG1900 ACCTCCTCCA CCGTGGACCC CGCGCGGTGC GGTGCGAGTC GGACTCATAG 1950GGGGCGCAGC GCGGGCTCGT GCTCCCGGTG ATACACACGC TTCACGTTCT 2000 GGCCGCGTCGGTACTGTTCG TGACGGTGTT CTTCATGGAC AGCCACGTCC 2050 GGGACCTTCG GGGAGCCGAGTGCGTCTTGA ACTGGCTGGA GGACCACTTG 2100 CACTCGCTGA GCGACCTCTA CGTCACGAACCACCGGCCTC GCGTGCGCGG 2150 GTCGTAGCAC ACCATGTTTC TGCTCTCCGA CGACCTCCTTTTCAGACCTC 2200 AGCTGAACCG CCTGAGGTTG GTCTTCGACT CGTAGGTCGC GCACGCGCTC2250 CTCCTACGCC CTGCGATAGA CACGTCGCAC ACGTTGCGGT TCCCGACGCA 2300GTTGAGGAGG CGGTCGCACC GGCACCTTCC GAGGCTCCTA TTCCCGTCGT 2350 ACCTCTAGCACTAGGAACAG CCATGGCCGC AGTAGCGACA GAAGAAGACC 2400 CAGGAGGAGG AGGAGTAGAAGACATTGTAC TCCTCCGGCC GGGTGCGTCT 2450 GTAGTTCTGC CCGATGGACA GGTAGTAGTACCTGGGGCCC CTCCACGGAG 2500 ACCTCCTCGT TACGCTTATG GACAGGATGC TACGGTCGGTCACCCTTAAG 2550 GGGGCTCTCG CCGACGTGGA CCCCTCTCAC GAGCCGATGC CGCGGAAGCC2600 CTTCCACCAC CTTCGGAGGC GAAAGCCGTA GGTGTTCCCG TCGTCGACAC 2650TGTGGCACCG GCACTTTTAC GACTTTCTCC CGCGGTGCCG GTCGCTCGTG 2700 GCGCGCGACTACAGCCTCGA GTTCTAGGAG TAAGTGTAGC CGTTGGTGGA 2750 GTTGCACCAG TTGGAGGAGCCCCGCACGTG GTTCGGCGTC CCGGGGGAGT 2800 ACCACTAGCA CCTCAAGACG TTCATGCCGTTGGAGAGGTT GAAGGACGCG 2850 CGGTTCGCCC TGCGGAAGTC GGGGACGCGC CTCTTCAGAGGGCTCGTCGC 2900 GCCTGCGAAG GCGCGGTACC ACCTCGAGCG GTCCGACCTA GCCTCCGCCG2950 GCCCCTCGTC GCTGTCCCAG GAGAAGCGCG CCAAGAGCTT CTGGCTCCCG 3000CCTCGCTCCG CCCGAAGAGG TCTGGTTCTT CGACTCCTGG ACACCGACTC 3050 GGGCGACTGGTACCTTCTAG AACAGACGAT GTCGAAGGTC CACCGGTCTC 3100 CCTACCTCAA GGACCGAAGGGCTTTCACGT AGGTGTCTCT GGACCGACGA 3150 GCCTTGTAAG ACGACAGCCT TTCGCTGCACCACTTCTAGA CACTGAAACC 3200 GGAACGGGCC CTGTAGATGT TTCTGGGACT GATGCAGGCGTTCCCGTCAC 3250 GGGCCGACGG GGACTTCACC TACCGGGGAC TTTCGTAGAA GCTGTTCCAC3300 ATGTGGTGCG TCTCACTGCA CACCAGGAAA CCCCACGAAG AGACCCTCTA 3350GAAGAGAGAC CCCCGGAGGG GCATGGGACC CCACGTCTAG TTACTCCTCA 3400 AGACGGTCGCCGACTCTCTG CCGTGTTCCT ACTCCCGGGG CCTCGACCGG 3450 TGAGGGCGGT ATGCGGCGTAGTACGACTTG ACGACCAGGC CTCTGGGGTT 3500 CCGCTCTGGA CGTAAGAGCC TCGACCACCTCTAGGACCCC CTGGACGAGG 3550 TCCCGTCCCC GGACGTTCTC CTTCTCCTCC AGACGTACCGGGGCGCGTCG 3600 AGAGTCTCGA GTCTTCTCCC GTCGAAGAGC GTCCACAGGT GGTACCGGGA3650 TGTGTAGCGG GTCCGACTGC GACTCCTGTC GGGCGGTTCG GACGTCGCGG 3700TGTCGGACCG GCGGTCCATA ATGTTGACCC ACAGGAAAGG GCCCACGGAC 3750 CGGTCTCCCCGACTCTGGGC ACCAAGGAGG TCCTACTTCT GTAAACTCCT 3800 TAAGGGGTAC TGGGGTTGCTGGATGTTTCC GAGACACCTG TTGGTCTGTC 3850 TGTCACCCTA CCACGACCGG AGCCTCCTCAAACTCGTCTA TCTCTCGTCC 3900 GTATCTGTTC TTTCGCCGAA GTCCATCGAC TTCGTCTCTCTCTCTTCCGT 3950 CGTATGCAGT CGTAAAAGAA GAGACGTGAA TATTCTTTCT AGTTTCTGAA4000 ATTCTGAAAG CGATAAAGAA GACGATAGAT GATGTTTGAA GTTTCTCCTT 4050GGTCCTCCGG TTCTCCTCGT ACTTTCACCT GTTCCTCACA CTGGTGACTT 4100 CGTGGTGTCCCTCCCCAATC CGGAGGCCTA CTGACGCCCG TCCGGACCTA 4150 TTATAGGTCG GAGGGTGTTCTTCGACCACC TCGTCTCACA AGGGACTGAG 4200 GAGGTTCCTT TCCCTCTGCG GGAAAGTACCAGACGACTCA TTGTCCACGG 4250 AAGGGTCTGT GACCGCAATG ACGAACTGGT TTCTCGGGAGTTCGCCGGGA 4300 ATACGGTCGC ACTGTCTCCC GAGTGGAGAA CGGAAGATCC AGTGAAGAGT4350 GTTACAGGGA AGTCGTGGAC TGGGACACGG GCGGTCAATA AGGAACCATT 4400ATACTCATTA TGTAGTTTCT CATCA 4425 1298 amino acids Amino Acid Linear notprovided 33 Met Gln Arg Gly Ala Ala Leu Cys Leu Arg Leu Trp Leu Cys Leu1 5 10 15 Gly Leu Leu Asp Gly Leu Val Ser Gly Tyr Ser Met Thr Pro Pro 2025 30 Thr Leu Asn Ile Thr Glu Glu Ser His Val Ile Asp Thr Gly Asp 35 4045 Ser Leu Ser Ile Ser Cys Arg Gly Gln His Pro Leu Glu Trp Ala 50 55 60Trp Pro Gly Ala Gln Glu Ala Pro Ala Thr Gly Asp Lys Asp Ser 65 70 75 GluAsp Thr Gly Val Val Arg Asp Cys Glu Gly Thr Asp Ala Arg 80 85 90 Pro TyrCys Lys Val Leu Leu Leu His Glu Val His Ala Asn Asp 95 100 105 Thr GlySer Tyr Val Cys Tyr Tyr Lys Tyr Ile Lys Ala Arg Ile 110 115 120 Glu GlyThr Thr Ala Ala Ser Ser Tyr Val Phe Val Arg Asp Phe 125 130 135 Glu GlnPro Phe Ile Asn Lys Pro Asp Thr Leu Leu Val Asn Arg 140 145 150 Lys AspAla Met Trp Val Pro Cys Leu Val Ser Ile Pro Gly Leu 155 160 165 Asn ValThr Leu Arg Ser Gln Ser Ser Val Leu Trp Pro Asp Gly 170 175 180 Gln GluVal Val Trp Asp Asp Arg Arg Gly Met Leu Val Ser Thr 185 190 195 Pro LeuLeu His Asp Ala Leu Tyr Leu Gln Cys Glu Thr Thr Trp 200 205 210 Gly AspGln Asp Phe Leu Ser Asn Pro Phe Leu Val His Ile Thr 215 220 225 Gly AsnGlu Leu Tyr Asp Ile Gln Leu Leu Pro Arg Lys Ser Leu 230 235 240 Glu LeuLeu Val Gly Glu Lys Leu Val Leu Asn Cys Thr Val Trp 245 250 255 Ala GluPhe Asn Ser Gly Val Thr Phe Asp Trp Asp Tyr Pro Gly 260 265 270 Lys GlnAla Glu Arg Gly Lys Trp Val Pro Glu Arg Arg Ser Gln 275 280 285 Gln ThrHis Thr Glu Leu Ser Ser Ile Leu Thr Ile His Asn Val 290 295 300 Ser GlnHis Asp Leu Gly Ser Tyr Val Cys Lys Ala Asn Asn Gly 305 310 315 Ile GlnArg Phe Arg Glu Ser Thr Glu Val Ile Val His Glu Asn 320 325 330 Pro PheIle Ser Val Glu Trp Leu Lys Gly Pro Ile Leu Glu Ala 335 340 345 Thr AlaGly Asp Glu Leu Val Lys Leu Pro Val Lys Leu Ala Ala 350 355 360 Tyr ProPro Pro Glu Phe Gln Trp Tyr Lys Asp Gly Lys Ala Leu 365 370 375 Ser GlyArg His Ser Pro His Ala Leu Val Leu Lys Glu Val Thr 380 385 390 Glu AlaSer Thr Gly Thr Tyr Thr Leu Ala Leu Trp Asn Ser Ala 395 400 405 Ala GlyLeu Arg Arg Asn Ile Ser Leu Glu Leu Val Val Asn Val 410 415 420 Pro ProGln Ile His Glu Lys Glu Ala Ser Ser Pro Ser Ile Tyr 425 430 435 Ser ArgHis Ser Arg Gln Ala Leu Thr Cys Thr Ala Tyr Gly Val 440 445 450 Pro LeuPro Leu Ser Ile Gln Trp His Trp Arg Pro Trp Thr Pro 455 460 465 Cys LysMet Phe Ala Gln Arg Ser Leu Arg Arg Arg Gln Gln Gln 470 475 480 Asp LeuMet Pro Gln Cys Arg Asp Trp Arg Ala Val Thr Thr Gln 485 490 495 Asp AlaVal Asn Pro Ile Glu Ser Leu Asp Thr Trp Thr Glu Phe 500 505 510 Val GluGly Lys Asn Lys Thr Val Ser Lys Leu Val Ile Gln Asn 515 520 525 Ala AsnVal Ser Ala Met Tyr Lys Cys Val Val Ser Asn Lys Val 530 535 540 Gly GlnAsp Glu Arg Leu Ile Tyr Phe Tyr Val Thr Thr Ile Pro 545 550 555 Asp GlyPhe Thr Ile Glu Ser Lys Pro Ser Glu Glu Leu Leu Glu 560 565 570 Gly GlnPro Val Leu Leu Ser Cys Gln Ala Asp Ser Tyr Lys Tyr 575 580 585 Glu HisLeu Arg Trp Tyr Arg Leu Asn Leu Ser Thr Leu His Asp 590 595 600 Ala HisGly Asn Pro Leu Leu Leu Asp Cys Lys Asn Val His Leu 605 610 615 Phe AlaThr Pro Leu Ala Ala Ser Leu Glu Glu Val Ala Pro Gly 620 625 630 Ala ArgHis Ala Thr Leu Ser Leu Ser Ile Pro Arg Val Ala Pro 635 640 645 Glu HisGlu Gly His Tyr Val Cys Glu Val Gln Asp Arg Arg Ser 650 655 660 His AspLys His Cys His Lys Lys Tyr Leu Ser Val Gln Ala Leu 665 670 675 Glu AlaPro Arg Leu Thr Gln Asn Leu Thr Asp Leu Leu Val Asn 680 685 690 Val SerAsp Ser Leu Glu Met Gln Cys Leu Val Ala Gly Ala His 695 700 705 Ala ProSer Ile Val Trp Tyr Lys Asp Glu Arg Leu Leu Glu Glu 710 715 720 Lys SerGly Val Asp Leu Ala Asp Ser Asn Gln Lys Leu Ser Ile 725 730 735 Gln ArgVal Arg Glu Glu Asp Ala Gly Arg Tyr Leu Cys Ser Val 740 745 750 Cys AsnAla Lys Gly Cys Val Asn Ser Ser Ala Ser Val Ala Val 755 760 765 Glu GlySer Glu Asp Lys Gly Ser Met Glu Ile Val Ile Leu Val 770 775 780 Gly ThrGly Val Ile Ala Val Phe Phe Trp Val Leu Leu Leu Leu 785 790 795 Ile PheCys Asn Met Arg Arg Pro Ala His Ala Asp Ile Lys Thr 800 805 810 Gly TyrLeu Ser Ile Ile Met Asp Pro Gly Glu Val Pro Leu Glu 815 820 825 Glu GlnCys Glu Tyr Leu Ser Tyr Asp Ala Ser Gln Trp Glu Phe 830 835 840 Pro ArgGlu Arg Leu His Leu Gly Arg Val Leu Gly Tyr Gly Ala 845 850 855 Phe GlyLys Val Val Glu Ala Ser Ala Phe Gly Ile His Lys Gly 860 865 870 Ser SerCys Asp Thr Val Ala Val Lys Met Leu Lys Glu Gly Ala 875 880 885 Thr AlaSer Glu His Arg Ala Leu Met Ser Glu Leu Lys Ile Leu 890 895 900 Ile HisIle Gly Asn His Leu Asn Val Val Asn Leu Leu Gly Ala 905 910 915 Cys ThrLys Pro Gln Gly Pro Leu Met Val Ile Val Glu Phe Cys 920 925 930 Lys TyrGly Asn Leu Ser Asn Phe Leu Arg Ala Lys Arg Asp Ala 935 940 945 Phe SerPro Cys Ala Glu Lys Ser Pro Glu Gln Arg Gly Arg Phe 950 955 960 Arg AlaMet Val Glu Leu Ala Arg Leu Asp Arg Arg Arg Pro Gly 965 970 975 Ser SerAsp Arg Val Leu Phe Ala Arg Phe Ser Lys Thr Glu Gly 980 985 990 Gly AlaArg Arg Ala Ser Pro Asp Gln Glu Ala Glu Asp Leu Trp 995 1000 1005 LeuSer Pro Leu Thr Met Glu Asp Leu Val Cys Tyr Ser Phe Gln 1010 1015 1020Val Ala Arg Gly Met Glu Phe Leu Ala Ser Arg Lys Cys Ile His 1025 10301035 Arg Asp Leu Ala Ala Arg Asn Ile Leu Leu Ser Glu Ser Asp Val 10401045 1050 Val Lys Ile Cys Asp Phe Gly Leu Ala Arg Asp Ile Tyr Lys Asp1055 1060 1065 Pro Asp Tyr Val Arg Lys Gly Ser Ala Arg Leu Pro Leu LysTrp 1070 1075 1080 Met Ala Pro Glu Ser Ile Phe Asp Lys Val Tyr Thr ThrGln Ser 1085 1090 1095 Asp Val Trp Ser Phe Gly Val Leu Leu Trp Glu IlePhe Ser Leu 1100 1105 1110 Gly Ala Ser Pro Tyr Pro Gly Val Gln Ile AsnGlu Glu Phe Cys 1115 1120 1125 Gln Arg Leu Arg Asp Gly Thr Arg Met ArgAla Pro Glu Leu Ala 1130 1135 1140 Thr Pro Ala Ile Arg Arg Ile Met LeuAsn Cys Trp Ser Gly Asp 1145 1150 1155 Pro Lys Ala Arg Pro Ala Phe SerGlu Leu Val Glu Ile Leu Gly 1160 1165 1170 Asp Leu Leu Gln Gly Arg GlyLeu Gln Glu Glu Glu Glu Val Cys 1175 1180 1185 Met Ala Pro Arg Ser SerGln Ser Ser Glu Glu Gly Ser Phe Ser 1190 1195 1200 Gln Val Ser Thr MetAla Leu His Ile Ala Gln Ala Asp Ala Glu 1205 1210 1215 Asp Ser Pro ProSer Leu Gln Arg His Ser Leu Ala Ala Arg Tyr 1220 1225 1230 Tyr Asn TrpVal Ser Phe Pro Gly Cys Leu Ala Arg Gly Ala Glu 1235 1240 1245 Thr ArgGly Ser Ser Arg Met Lys Thr Phe Glu Glu Phe Pro Met 1250 1255 1260 ThrPro Thr Thr Tyr Lys Gly Ser Val Asp Asn Gln Thr Asp Ser 1265 1270 1275Gly Met Val Leu Ala Ser Glu Glu Phe Glu Gln Ile Glu Ser Arg 1280 12851290 His Arg Gln Glu Ser Gly Phe Arg 1295 1298 3348 base pairs NucleicAcid Single Linear not provided 34 ATGGCTGGGA TTTTCTATTT CGCCCTATTTTCGTGTCTCT TCGGGATTTG 50 CGACGCTGTC ACAGGTTCCA GGGTATACCC CGCGAATGAAGTTACCTTAT 100 TGGATTCCAG ATCTGTTCAG GGAGAACTTG GGTGGATAGC AAGCCCTCTG150 GAAGGAGGGT GGGAGGAAGT GAGTATCATG GATGAAAAAA ATACACCAAT 200CCGAACCTAC CAAGTGTGCA ATGTGATGGA ACCCAGCCAG AATAACTGGC 250 TACGAACTGATTGGATCACC CGAGAAGGGG CTCAGAGGGT GTATATTGAG 300 ATTAAATTCA CCTTGAGGGACTGCAATAGT CTTCCGGGCG TCATGGGGAC 350 TTGCAAGGAG ACGTTTAACC TGTACTACTATGAATCAGAC AACGACAAAG 400 AGCGTTTCAT CAGAGAGAAC CAGTTTGTCA AAATTGACACCATTGCTGCT 450 GATGAGAGCT TCACCCAAGT GGACATTGGT GACAGAATCA TGAAGCTGAA500 CACCGAGATC CGGGATGTAG GGCCATTAAG CAAAAAGGGG TTTTACCTGG 550CTTTTCAGGA TGTGGGGGCC TGCATCGCCC TGGTATCAGT CCGTGTGTTC 600 TATAAAAAGTGTCCACTCAC AGTCCGCAAT CTGGCCCAGT TTCCTGACAC 650 CATCACAGGG GCTGATACGTCTTCCCTGGT GGAAGTTCGA GGCTCCTGTG 700 TCAACAACTC AGAAGAGAAA GATGTGCCAAAAATGTACTG TGGGGCAGAT 750 GGTGAATGGC TGGTACCCAT TGGCAACTGC CTATGCAACGCTGGGCATGA 800 GGAGCGGAGC GGAGAATGCC AAGCTTGCAA AATTGGATAT TACAAGGCTC850 TCTCCACGGA TGCCACCTGT GCCAAGTGCC CACCCCACAG CTACTCTGTC 900TGGGAAGGAG CCACCTCGTG CACCTGTGAC CGAGGCTTTT TCAGAGCTGA 950 CAACGATGCTGCCTCTATGC CCTGCACCCG TCCACCATCT GCTCCCCTGA 1000 ACTTGATTTC AAATGTCAACGAGACATCTG TGAACTTGGA ATGGAGTAGC 1050 CCTCAGAATA CAGGTGGCCG CCAGGACATTTCCTATAATG TGGTATGCAA 1100 GAAATGTGGA GCTGGTGACC CCAGCAAGTG CCGACCCTGTGGAAGTGGGG 1150 TCCACTACAC CCCACAGCAG AATGGCTTGA AGACCACCAA AGGCTCCATC1200 ACTGACCTCC TAGCTCATAC CAATTACACC TTTGAAATCT GGGCTGTGAA 1250TGGAGTGTCC AAATATAACC CTAACCCAGA CCAATCAGTT TCTGTCACTG 1300 TGACCACCAACCAAGCAGCA CCATCATCCA TTGCTTTGGT CCAGGCTAAA 1350 GAAGTCACAA GATACAGTGTGGCACTGGCT TGGCTGGAAC CAGATCGGCC 1400 CAATGGGGTA ATCCTGGAAT ATGAAGTCAAGTATTATGAG AAGGATCAGA 1450 ATGAGCGAAG CTATCGTATA GTTCGGACAG CTGCCAGGAACACAGATATC 1500 AAAGGCCTGA ACCCTCTCAC TTCCTATGTT TTCCACGTGC GAGCCAGGAC1550 AGCAGCTGGC TATGGAGACT TCAGTGAGCC CTTGGAGGTT ACAACCAACA 1600CAGTGCCTTC CCGGATCATT GGAGATGGGG CTAACTCCAC AGTCCTTCTG 1650 GTCTCTGTCTCGGGCAGTGT GGTGCTGGTG GTAATTCTCA TTGCAGCTTT 1700 TGTCATCAGC CGGAGACGGAGTAAATACAG TAAAGCCAAA CAAGAAGCGG 1750 ATGAAGAGAA ACATTTGAAT CAAGGTGTAAGAACATATGT GGACCCCTTT 1800 ACGTACGAAG ATCCCAACCA AGCAGTGCGA GAGTTTGCCAAAGAAATTGA 1850 CGCATCCTGC ATTAAGATTG AAAAAGTTAT AGGAGTTGGT GAATTTGGTG1900 AGGTATGCAG TGGGCGTCTC AAAGTGCCTG GCAAGAGAGA GATCTGTGTG 1950GCTATCAAGA CTCTGAAAGC TGGTTATACA GACAAACAGA GGAGAGACTT 2000 CCTGAGTGAGGCCAGCATCA TGGGACAGTT TGACCATCCG AACATCATTC 2050 ACTTGGAAGG CGTGGTCACTAAATGTAAAC CAGTAATGAT CATAACAGAG 2100 TACATGGAGA ATGGCTCCTT GGATGCATTCCTCAGGAAAA ATGATGGCAG 2150 ATTTACAGTC ATTCAGCTGG TGGGCATGCT TCGTGGCATTGGGTCTGGGA 2200 TGAAGTATTT ATCTGATATG AGCTATGTGC ATCGTGATCT GGCCGCACGG2250 AACATCCTGG TGAACAGCAA CTTGGTCTGC AAAGTGTCTG ATTTTGGCAT 2300GTCCCGAGTG CTTGAGGATG ATCCGGAAGC AGCTTACACC ACCAGGGGTG 2350 GCAAGATTCCTATCCGGTGG ACTGCGCCAG AAGCAATTGC CTATCGTAAA 2400 TTCACATCAG CAAGTGATGTATGGAGCTAT GGAATCGTTA TGTGGGAAGT 2450 GATGTCGTAC GGGGAGAGGC CCTATTGGGATATGTCCAAT CAAGATGTGA 2500 TTAAAGCCAT TGAGGAAGGC TATCGGTTAC CCCCTCCAATGGACTGCCCC 2550 ATTGCGCTCC ACCAGCTGAT GCTAGACTGC TGGCAGAAGG AGAGGAGCGA2600 CAGGCCTAAA TTTGGGCAGA TTGTCAACAT GTTGGACAAA CTCATCCGCA 2650ACCCCAACAG CTTGAAGAGG ACAGGGACGG AGAGCTCCAG ACCTAACACT 2700 GCCTTGTTGGATCCAAGCTC CCCTGAATTC TCTGCTGTGG TATCAGTGGG 2750 CGATTGGCTC CAGGCCATTAAAATGGACCG GTATAAGGAT AACTTCACAG 2800 CTGCTGGTTA TACCACACTA GAGGCTGTGGTGCACGTGAA CCAGGAGGAC 2850 CTGGCAAGAA TTGGTATCAC AGCCATCACA CACCAGAATAAGATTTTGAG 2900 CAGTGTCCAG GCAATGCGAA CCCAAATGCA GCAGATGCAC GGCAGAATGG2950 TTCCCGTCTG AGCCAGTACT GAATAAACTC AAAACTCTTG AAATTAGTTT 3000ACCTCATCCA TGCACTTTAA TTGAAGAACT GCACTTTTTT TACTTCGTCT 3050 TCGCCCTCTGAAATTAAAGA AATGAAAAAA AAAAAACAAT ATCTGCAGCG 3100 TTGCTTGGTG CACAGATTGCTGAAACTGTG GGGCTTACAG AAATGACTGC 3150 CGGTCATTTG AATGAGACCT GGAACAAATCGTTTCTCAGA AGTACTTTTC 3200 TGTTCATCAC CAGTCTGTAA AATACATGTA CCTATAGAAATAGAACACTG 3250 CCTCTGAGTT TTGATGCTGT ATTTGCTGCC AGACACTGAG CTTCTGAGAC3300 ATCCCTGATT CTCTCTCCAT TTGGAATTAC AACGGTCGAC GAGCTCGA 3348 3348 basepairs Nucleic Acid Single Linear not provided 35 TACCGACCCT AAAAGATAAAGCGGGATAAA AGCACAGAGA AGCCCTAAAC 50 GCTGCGACAG TGTCCAAGGT CCCATATGGGGCGCTTACTT CAATGGAATA 100 ACCTAAGGTC TAGACAAGTC CCTCTTGAAC CCACCTATCGTTCGGGAGAC 150 CTTCCTCCCA CCCTCCTTCA CTCATAGTAC CTACTTTTTT TATGTGGTTA200 GGCTTGGATG GTTCACACGT TACACTACCT TGGGTCGGTC TTATTGACCG 250ATGCTTGACT AACCTAGTGG GCTCTTCCCC GAGTCTCCCA CATATAACTC 300 TAATTTAAGTGGAACTCCCT GACGTTATCA GAAGGCCCGC AGTACCCCTG 350 AACGTTCCTC TGCAAATTGGACATGATGAT ACTTAGTCTG TTGCTGTTTC 400 TCGCAAAGTA GTCTCTCTTG GTCAAACAGTTTTAACTGTG GTAACGACGA 450 CTACTCTCGA AGTGGGTTCA CCTGTAACCA CTGTCTTAGTACTTCGACTT 500 GTGGCTCTAG GCCCTACATC CCGGTAATTC GTTTTTCCCC AAAATGGACC550 GAAAAGTCCT ACACCCCCGG ACGTAGCGGG ACCATAGTCA GGCACACAAG 600ATATTTTTCA CAGGTGAGTG TCAGGCGTTA GACCGGGTCA AAGGACTGTG 650 GTAGTGTCCCCGACTATGCA GAAGGGACCA CCTTCAAGCT CCGAGGACAC 700 AGTTGTTGAG TCTTCTCTTTCTACACGGTT TTTACATGAC ACCCCGTCTA 750 CCACTTACCG ACCATGGGTA ACCGTTGACGGATACGTTGC GACCCGTACT 800 CCTCGCCTCG CCTCTTACGG TTCGAACGTT TTAACCTATAATGTTCCGAG 850 AGAGGTGCCT ACGGTGGACA CGGTTCACGG GTGGGGTGTC GATGAGACAG900 ACCCTTCCTC GGTGGAGCAC GTGGACACTG GCTCCGAAAA AGTCTCGACT 950GTTGCTACGA CGGAGATACG GGACGTGGGC AGGTGGTAGA CGAGGGGACT 1000 TGAACTAAAGTTTACAGTTG CTCTGTAGAC ACTTGAACCT TACCTCATCG 1050 GGAGTCTTAT GTCCACCGGCGGTCCTGTAA AGGATATTAC ACCATACGTT 1100 CTTTACACCT CGACCACTGG GGTCGTTCACGGCTGGGACA CCTTCACCCC 1150 AGGTGATGTG GGGTGTCGTC TTACCGAACT TCTGGTGGTTTCCGAGGTAG 1200 TGACTGGAGG ATCGAGTATG GTTAATGTGG AAACTTTAGA CCCGACACTT1250 ACCTCACAGG TTTATATTGG GATTGGGTCT GGTTAGTCAA AGACAGTGAC 1300ACTGGTGGTT GGTTCGTCGT GGTAGTAGGT AACGAAACCA GGTCCGATTT 1350 CTTCAGTGTTCTATGTCACA CCGTGACCGA ACCGACCTTG GTCTAGCCGG 1400 GTTACCCCAT TAGGACCTTATACTTCAGTT CATAATACTC TTCCTAGTCT 1450 TACTCGCTTC GATAGCATAT CAAGCCTGTCGACGGTCCTT GTGTCTATAG 1500 TTTCCGGACT TGGGAGAGTG AAGGATACAA AAGGTGCACGCTCGGTCCTG 1550 TCGTCGACCG ATACCTCTGA AGTCACTCGG GAACCTCCAA TGTTGGTTGT1600 GTCACGGAAG GGCCTAGTAA CCTCTACCCC GATTGAGGTG TCAGGAAGAC 1650CAGAGACAGA GCCCGTCACA CCACGACCAC CATTAAGAGT AACGTCGAAA 1700 ACAGTAGTCGGCCTCTGCCT CATTTATGTC ATTTCGGTTT GTTCTTCGCC 1750 TACTTCTCTT TGTAAACTTAGTTCCACATT CTTGTATACA CCTGGGGAAA 1800 TGCATGCTTC TAGGGTTGGT TCGTCACGCTCTCAAACGGT TTCTTTAACT 1850 GCGTAGGACG TAATTCTAAC TTTTTCAATA TCCTCAACCACTTAAACCAC 1900 TCCATACGTC ACCCGCAGAG TTTCACGGAC CGTTCTCTCT CTAGACACAC1950 CGATAGTTCT GAGACTTTCG ACCAATATGT CTGTTTGTCT CCTCTCTGAA 2000GGACTCACTC CGGTCGTAGT ACCCTGTCAA ACTGGTAGGC TTGTAGTAAG 2050 TGAACCTTCCGCACCAGTGA TTTACATTTG GTCATTACTA GTATTGTCTC 2100 ATGTACCTCT TACCGAGGAACCTACGTAAG GAGTCCTTTT TACTACCGTC 2150 TAAATGTCAG TAAGTCGACC ACCCGTACGAAGCACCGTAA CCCAGACCCT 2200 ACTTCATAAA TAGACTATAC TCGATACACG TAGCACTAGACCGGCGTGCC 2250 TTGTAGGACC ACTTGTCGTT GAACCAGACG TTTCACAGAC TAAAACCGTA2300 CAGGGCTCAC GAACTCCTAC TAGGCCTTCG TCGAATGTGG TGGTCCCCAC 2350CGTTCTAAGG ATAGGCCACC TGACGCGGTC TTCGTTAACG GATAGCATTT 2400 AAGTGTAGTCGTTCACTACA TACCTCGATA CCTTAGCAAT ACACCCTTCA 2450 CTACAGCATG CCCCTCTCCGGGATAACCCT ATACAGGTTA GTTCTACACT 2500 AATTTCGGTA ACTCCTTCCG ATAGCCAATGGGGGAGGTTA CCTGACGGGG 2550 TAACGCGAGG TGGTCGACTA CGATCTGACG ACCGTCTTCCTCTCCTCGCT 2600 GTCCGGATTT AAACCCGTCT AACAGTTGTA CAACCTGTTT GAGTAGGCGT2650 TGGGGTTGTC GAACTTCTCC TGTCCCTGCC TCTCGAGGTC TGGATTGTGA 2700CGGAACAACC TAGGTTCGAG GGGACTTAAG AGACGACACC ATAGTCACCC 2750 GCTAACCGAGGTCCGGTAAT TTTACCTGGC CATATTCCTA TTGAAGTGTC 2800 GACGACCAAT ATGGTGTGATCTCCGACACC ACGTGCACTT GGTCCTCCTG 2850 GACCGTTCTT AACCATAGTG TCGGTAGTGTGTGGTCTTAT TCTAAAACTC 2900 GTCACAGGTC CGTTACGCTT GGGTTTACGT CGTCTACGTGCCGTCTTACC 2950 AAGGGCAGAC TCGGTCATGA CTTATTTGAG TTTTGAGAAC TTTAATCAAA3000 TGGAGTAGGT ACGTGAAATT AACTTCTTGA CGTGAAAAAA ATGAAGCAGA 3050AGCGGGAGAC TTTAATTTCT TTACTTTTTT TTTTTTGTTA TAGACGTCGC 3100 AACGAACCACGTGTCTAACG ACTTTGACAC CCCGAATGTC TTTACTGACG 3150 GCCAGTAAAC TTACTCTGGACCTTGTTTAG CAAAGAGTCT TCATGAAAAG 3200 ACAAGTAGTG GTCAGACATT TTATGTACATGGATATCTTT ATCTTGTGAC 3250 GGAGACTCAA AACTACGACA TAAACGACGG TCTGTGACTCGAAGACTCTG 3300 TAGGGACTAA GAGAGAGGTA AACCTTAATG TTGCCAGCTG CTCGAGCT3348 1104 amino acids Amino Acid Linear not provided 36 Met Ala Gly IlePhe Tyr Phe Ala Leu Phe Ser Cys Leu Phe Gly 1 5 10 15 Ile Cys Asp AlaVal Thr Gly Ser Arg Val Tyr Pro Ala Asn Glu 20 25 30 Val Thr Leu Leu AspSer Arg Ser Val Gln Gly Glu Leu Gly Trp 35 40 45 Ile Ala Ser Pro Leu GluGly Gly Trp Glu Glu Val Ser Ile Met 50 55 60 Asp Glu Lys Asn Thr Pro IleArg Thr Tyr Gln Val Cys Asn Val 65 70 75 Met Glu Pro Ser Gln Asn Asn TrpLeu Arg Thr Asp Trp Ile Thr 80 85 90 Arg Glu Gly Ala Gln Arg Val Tyr IleGlu Ile Lys Phe Thr Leu 95 100 105 Arg Asp Cys Asn Ser Leu Pro Gly ValMet Gly Thr Cys Lys Glu 110 115 120 Thr Phe Asn Leu Tyr Tyr Tyr Glu SerAsp Asn Asp Lys Glu Arg 125 130 135 Phe Ile Arg Glu Asn Gln Phe Val LysIle Asp Thr Ile Ala Ala 140 145 150 Asp Glu Ser Phe Thr Gln Val Asp IleGly Asp Arg Ile Met Lys 155 160 165 Leu Asn Thr Glu Ile Arg Asp Val GlyPro Leu Ser Lys Lys Gly 170 175 180 Phe Tyr Leu Ala Phe Gln Asp Val GlyAla Cys Ile Ala Leu Val 185 190 195 Ser Val Arg Val Phe Tyr Lys Lys CysPro Leu Thr Val Arg Asn 200 205 210 Leu Ala Gln Phe Pro Asp Thr Ile ThrGly Ala Asp Thr Ser Ser 215 220 225 Leu Val Glu Val Arg Gly Ser Cys ValAsn Asn Ser Glu Glu Lys 230 235 240 Asp Val Pro Lys Met Tyr Cys Gly AlaAsp Gly Glu Trp Leu Val 245 250 255 Pro Ile Gly Asn Cys Leu Cys Asn AlaGly His Glu Glu Arg Ser 260 265 270 Gly Glu Cys Gln Ala Cys Lys Ile GlyTyr Tyr Lys Ala Leu Ser 275 280 285 Thr Asp Ala Thr Cys Ala Lys Cys ProPro His Ser Tyr Ser Val 290 295 300 Trp Glu Gly Ala Thr Ser Cys Thr CysAsp Arg Gly Phe Phe Arg 305 310 315 Ala Asp Asn Asp Ala Ala Ser Met ProCys Thr Arg Pro Pro Ser 320 325 330 Ala Pro Leu Asn Leu Ile Ser Asn ValAsn Glu Thr Ser Val Asn 335 340 345 Leu Glu Trp Ser Ser Pro Gln Asn ThrGly Gly Arg Gln Asp Ile 350 355 360 Ser Tyr Asn Val Val Cys Lys Lys CysGly Ala Gly Asp Pro Ser 365 370 375 Lys Cys Arg Pro Cys Gly Ser Gly ValHis Tyr Thr Pro Gln Gln 380 385 390 Asn Gly Leu Lys Thr Thr Lys Gly SerIle Thr Asp Leu Leu Ala 395 400 405 His Thr Asn Tyr Thr Phe Glu Ile TrpAla Val Asn Gly Val Ser 410 415 420 Lys Tyr Asn Pro Asn Pro Asp Gln SerVal Ser Val Thr Val Thr 425 430 435 Thr Asn Gln Ala Ala Pro Ser Ser IleAla Leu Val Gln Ala Lys 440 445 450 Glu Val Thr Arg Tyr Ser Val Ala LeuAla Trp Leu Glu Pro Asp 455 460 465 Arg Pro Asn Gly Val Ile Leu Glu TyrGlu Val Lys Tyr Tyr Glu 470 475 480 Lys Asp Gln Asn Glu Arg Ser Tyr ArgIle Val Arg Thr Ala Ala 485 490 495 Arg Asn Thr Asp Ile Lys Gly Leu AsnPro Leu Thr Ser Tyr Val 500 505 510 Phe His Val Arg Ala Arg Thr Ala AlaGly Tyr Gly Asp Phe Ser 515 520 525 Glu Pro Leu Glu Val Thr Thr Asn ThrVal Pro Ser Arg Ile Ile 530 535 540 Gly Asp Gly Ala Asn Ser Thr Val LeuLeu Val Ser Val Ser Gly 545 550 555 Ser Val Val Leu Val Val Ile Leu IleAla Ala Phe Val Ile Ser 560 565 570 Arg Arg Arg Ser Lys Tyr Ser Lys AlaLys Gln Glu Ala Asp Glu 575 580 585 Glu Lys His Leu Asn Gln Gly Val ArgThr Tyr Val Asp Pro Phe 590 595 600 Thr Tyr Glu Asp Pro Asn Gln Ala ValArg Glu Phe Ala Lys Glu 605 610 615 Ile Asp Ala Ser Cys Ile Lys Ile GluLys Val Ile Gly Val Gly 620 625 630 Glu Phe Gly Glu Val Cys Ser Gly ArgLeu Lys Val Pro Gly Lys 635 640 645 Arg Glu Ile Cys Val Ala Ile Lys ThrLeu Lys Ala Gly Tyr Thr 650 655 660 Asp Lys Gln Arg Arg Asp Phe Leu SerGlu Ala Ser Ile Met Gly 665 670 675 Gln Phe Asp His Pro Asn Ile Ile HisLeu Glu Gly Val Val Thr 680 685 690 Lys Cys Lys Pro Val Met Ile Ile ThrGlu Tyr Met Glu Asn Gly 695 700 705 Ser Leu Asp Ala Phe Leu Arg Lys AsnAsp Gly Arg Phe Thr Val 710 715 720 Ile Gln Leu Val Gly Met Leu Arg GlyIle Gly Ser Gly Met Lys 725 730 735 Tyr Leu Ser Asp Met Ser Tyr Val HisArg Asp Leu Ala Ala Arg 740 745 750 Asn Ile Leu Val Asn Ser Asn Leu ValCys Lys Val Ser Asp Phe 755 760 765 Gly Met Ser Arg Val Leu Glu Asp AspPro Glu Ala Ala Tyr Thr 770 775 780 Thr Arg Gly Gly Lys Ile Pro Ile ArgTrp Thr Ala Pro Glu Ala 785 790 795 Ile Ala Tyr Arg Lys Phe Thr Ser AlaSer Asp Val Trp Ser Tyr 800 805 810 Gly Ile Val Met Trp Glu Val Met SerTyr Gly Glu Arg Pro Tyr 815 820 825 Trp Asp Met Ser Asn Gln Asp Val IleLys Ala Ile Glu Glu Gly 830 835 840 Tyr Arg Leu Pro Pro Pro Met Asp CysPro Ile Ala Leu His Gln 845 850 855 Leu Met Leu Asp Cys Trp Gln Lys GluArg Ser Asp Arg Pro Lys 860 865 870 Phe Gly Gln Ile Val Asn Met Leu AspLys Leu Ile Arg Asn Pro 875 880 885 Asn Ser Leu Lys Arg Thr Gly Thr GluSer Ser Arg Pro Asn Thr 890 895 900 Ala Leu Leu Asp Pro Ser Ser Pro GluPhe Ser Ala Val Val Ser 905 910 915 Val Gly Asp Trp Leu Gln Ala Ile LysMet Asp Arg Tyr Lys Asp 920 925 930 Asn Phe Thr Ala Ala Gly Tyr Thr ThrLeu Glu Ala Val Val His 935 940 945 Val Asn Gln Glu Asp Leu Ala Arg IleGly Ile Thr Ala Ile Thr 950 955 960 His Gln Asn Lys Ile Leu Ser Ser ValGln Ala Met Arg Thr Gln 965 970 975 Met Gln Gln Met His Gly Arg Met ValPro Val Ala Ser Thr Glu 980 985 990 Thr Gln Asn Ser Asn Phe Thr Ser SerMet His Phe Asn Arg Thr 995 1000 1005 Ala Leu Phe Leu Leu Arg Leu ArgPro Leu Lys Leu Lys Lys Lys 1010 1015 1020 Lys Lys Asn Asn Ile Cys SerVal Ala Trp Cys Thr Asp Cys Asn 1025 1030 1035 Cys Gly Ala Tyr Arg AsnAsp Cys Arg Ser Phe Glu Asp Leu Glu 1040 1045 1050 Gln Ile Val Ser GlnLys Tyr Phe Ser Val His His Gln Ser Val 1055 1060 1065 Lys Tyr Met TyrLeu Lys Asn Thr Ala Ser Glu Phe Cys Cys Ile 1070 1075 1080 Cys Cys GlnThr Leu Ser Phe Asp Ile Pro Asp Ser Leu Ser Ile 1085 1090 1095 Trp AsnTyr Asn Gly Arg Arg Ala Arg 1100 1104 24 base pairs Nucleic Acid SingleLinear not provided 37 TCGGATCCAC ACGNGACTCT TGGC 24 28 base pairsNucleic Acid Single Linear not provided 38 TCGGATCCAC TCAGNGACTCTTNGCNGC 28 32 base pairs Nucleic Acid Single Linear not provided 39CTCGAATTCC AGATAAGCGT ACCAGCACAG TC 32 32 base pairs Nucleic Acid SingleLinear not provided 40 CTCGAATTCC AGATATCCGT ACCATAACAG TC 32 13 aminoacids Amino Acid Linear not provided 41 Met Asp Tyr Lys Asp Asp Asp AspLys Lys Leu Ala Met 1 5 10 13 54 base pairs Nucleic Acid Single Linearnot provided 42 CCGGATATCA TGGACTACAA GGACGACGAT GACAAGAAGC TTGCCATGGA50 GCTC 54 22 base pairs Nucleic Acid Single Linear not provided 43AGGCTGCTGG AGGAAAAGTC TG 22 32 base pairs Nucleic Acid Single Linear notprovided 44 GGAGGGTGAC CTCCATGCTG CCCTTATCCT CG 32 9108 base pairsNucleic Acid Single Linear not provided 45 TTCGAGCTCG CCCGACATTGATTATTGACT AGTTATTAAT AGTAATCAAT 50 TACGGGGTCA TTAGTTCATA GCCCATATATGGAGTTCCGC GTTACATAAC 100 TTACGGTAAA TGGCCCGCCT GGCTGACCGC CCAACGACCCCCGCCCATTG 150 ACGTCAATAA TGACGTATGT TCCCATAGTA ACGCCAATAG GGACTTTCCA200 TTGACGTCAA TGGGTGGAGT ATTTACGGTA AACTGCCCAC TTGGCAGTAC 250ATCAAGTGTA TCATATGCCA AGTACGCCCC CTATTGACGT CAATGACGGT 300 AAATGGCCCGCCTGGCATTA TGCCCAGTAC ATGACCTTAT GGGACTTTCC 350 TACTTGGCAG TACATCTACGTATTAGTCAT CGCTATTACC ATGGTGATGC 400 GGTTTTGGCA GTACATCAAT GGGCGTGGATAGCGGTTTGA CTCACGGGGA 450 TTTCCAAGTC TCCACCCCAT TGACGTCAAT GGGAGTTTGTTTTGGCACCA 500 AAATCAACGG GACTTTCCAA AATGTCGTAA CAACTCCGCC CCATTGACGC550 AAATGGGCGG TAGGCGTGTA CGGTGGGAGG TCTATATAAG CAGAGCTCGT 600TTAGTGAACC GTCAGATCGC CTGGAGACGC CATCCACGCT GTTTTGACCT 650 CCATAGAAGACACCGGGACC GATCCAGCCT CCGCGGCCGG GAACGGTGCA 700 TTGGAACGCG GATTCCCCGTGCCAAGAGTG ACGTAAGTAC CGCCTATAGA 750 GTCTATAGGC CCACCCCCTT GGCTTCGTTAGAACGCGGCT ACAATTAATA 800 CATAACCTTA TGTATCATAC ACATACGATT TAGGTGACACTATAGAATAA 850 CATCCACTTT GCCTTTCTCT CCACAGGTGT CCACTCCCAG GTCCAACTGC900 ACCTCGGTTC TATCGATTGA ATTCGCGGCC GCTCGGGTCG GACCCACGCG 950CAGCGGCCGG AGATGCAGCG GGGCGCCGCG CTGTGCCTGC GACTGTGGCT 1000 CTGCCTGGGACTCCTGGACG GCCTGGTGAG TGGCTACTCC ATGACCCCCC 1050 CGACCTTGAA CATCACGGAGGAGTCACACG TCATCGACAC CGGTGACAGC 1100 CTGTCCATCT CCTGCAGGGG ACAGCACCCCCTCGAGTGGG CTTGGCCAGG 1150 AGCTCAGGAG GCGCCAGCCA CCGGAGACAA GGACAGCGAGGACACGGGGG 1200 TGGTGCGAGA CTGCGAGGGC ACAGACGCCA GGCCCTACTG CAAGGTGTTG1250 CTGCTGCACG AGGTACATGC CAACGACACA GGCAGCTACG TCTGCTACTA 1300CAAGTACATC AAGGCACGCA TCGAGGGCAC CACGGCCGCC AGCTCCTACG 1350 TGTTCGTGAGAGACTTTGAG CAGCCATTCA TCAACAAGCC TGACACGCTC 1400 TTGGTCAACA GGAAGGACGCCATGTGGGTG CCCTGTCTGG TGTCCATCCC 1450 CGGCCTCAAT GTCACGCTGC GCTCGCAAAGCTCGGTGCTG TGGCCAGACG 1500 GGCAGGAGGT GGTGTGGGAT GACCGGCGGG GCATGCTCGTGTCCACGCCA 1550 CTGCTGCACG ATGCCCTGTA CCTGCAGTGC GAGACCACCT GGGGAGACCA1600 GGACTTCCTT TCCAACCCCT TCCTGGTGCA CATCACAGGC AACGAGCTCT 1650ATGACATCCA GCTGTTGCCC AGGAAGTCGC TGGAGCTGCT GGTAGGGGAG 1700 AAGCTGGTCCTGAACTGCAC CGTGTGGGCT GAGTTTAACT CAGGTGTCAC 1750 CTTTGACTGG GACTACCCAGGGAAGCAGGC AGAGCGGGGT AAGTGGGTGC 1800 CCGAGCGACG CTCCCAGCAG ACCCACACAGAACTCTCCAG CATCCTGACC 1850 ATCCACAACG TCAGCCAGCA CGACCTGGGC TCGTATGTGTGCAAGGCCAA 1900 CAACGGCATC CAGCGATTTC GGGAGAGCAC CGAGGTCATT GTGCATGAAA1950 ATCCCTTCAT CAGCGTCGAG TGGCTCAAAG GACCCATCCT GGAGGCCACG 2000GCAGGAGACG AGCTGGTGAA GCTGCCCGTG AAGCTGGCAG CGTACCCCCC 2050 GCCCGAGTTCCAGTGGTACA AGGATGGAAA GGCACTGTCC GGGCGCCACA 2100 GTCCACATGC CCTGGTGCTCAAGGAGGTGA CAGAGGCCAG CACAGGCACC 2150 TACACCCTCG CCCTGTGGAA CTCCGCTGCTGGCCTGAGGC GCAACATCAG 2200 CCTGGAGCTG GTGGTGAATG TGCCCCCCCA GATACATGAGAAGGAGGCCT 2250 CCTCCCCCAG CATCTACTCG CGTCACAGCC GCCAGGCCCT CACCTGCACG2300 GCCTACGGGG TGCCCCTGCC TCTCAGCATC CAGTGGCACT GGCGGCCCTG 2350GACACCCTGC AAGATGTTTG CCCAGCGTAG TCTCCGGCGG CGGCAGCAGC 2400 AAGACCTCATGCCACAGTGC CGTGACTGGA GGGCGGTGAC CACGCAGGAT 2450 GCCGTGAACC CCATCGAGAGCCTGGACACC TGGACCGAGT TTGTGGAGGG 2500 AAAGAATAAG ACTGTGAGCA AGCTGGTGATCCAGAATGCC AACGTGTCTG 2550 CCATGTACAA GTGTGTGGTC TCCAACAAGG TGGGCCAGGATGAGCGGCTC 2600 ATCTACTTCT ATGTGACCAC CATCCCCGAC GGCTTCACCA TCGAATCCAA2650 GCCATCCGAG GAGCTACTAG AGGGCCAGCC GGTGCTCCTG AGCTGCCAAG 2700CCGACAGCTA CAAGTACGAG CATCTGCGCT GGTACCGCCT CAACCTGTCC 2750 ACGCTGCACGATGCGCACGG GAACCCGCTT CTGCTCGACT GCAAGAACGT 2800 GCATCTGTTC GCCACCCCTCTGGCCGCCAG CCTGGAGGAG GTGGCACCTG 2850 GGGCGCGCCA CGCCACGCTC AGCCTGAGTATCCCCCGCGT CGCGCCCGAG 2900 CACGAGGGCC ACTATGTGTG CGAAGTGCAA GACCGGCGCAGCCATGACAA 2950 GCACTGCCAC AAGAAGTACC TGTCGGTGCA GGCCCTGGAA GCCCCTCGGC3000 TCACGCAGAA CTTGACCGAC CTCCTGGTGA ACGTGAGCGA CTCGCTGGAG 3050ATGCAGTGCT TGGTGGCCGG AGCGCACGCG CCCAGCATCG TGTGGTACAA 3100 AGACGAGAGGCTGCTGGAGG AAAAGTCTGG AGTCGACTTG GCGGACTCCA 3150 ACCAGAAGCT GAGCATCCAGCGCGTGCGCG AGGAGGATGC GGGACGCTAT 3200 CTGTGCAGCG TGTGCAACGC CAAGGGCTGCGTCAACTCCT CCGCCAGCGT 3250 GGCCGTGGAA GGCTCCGAGG ATAAGGGCAG CATGGAGATCGTGATCCTTG 3300 TCGGTACCGG CGTCATCGCT GTCTTCTTCT GGGTCCTCCT CCTCCTCATC3350 TTCTGTAACA TGAGGAGGCC GGCCCACGCA GACATCAAGA CGGGCTACCT 3400GTCCATCATC ATGGACCCCG GGGAGGTGCC TCTGGAGGAG CAATGCGAAT 3450 ACCTGTCCTACGATGCCAGC CAGTGGGAAT TCCCCCGAGA GCGGCTGCAC 3500 CTGGGGAGAG TGCTCGGCTACGGCGCCTTC GGGAAGGTGG TGGAAGCCTC 3550 CGCTTTCGGC ATCCACAAGG GCAGCAGCTGTGACACCGTG GCCGTGAAAA 3600 TGCTGAAAGA GGGCGCCACG GCCAGCGAGC ACCGCGCGCTGATGTCGGAG 3650 CTCAAGATCC TCATTCACAT CGGCAACCAC CTCAACGTGG TCAACCTCCT3700 CGGGGCGTGC ACCAAGCCGC AGGGCCCCCT CATGGTGATC GTGGAGTTCT 3750GCAAGTACGG CAACCTCTCC AACTTCCTGC GCGCCAAGCG GGACGCCTTC 3800 AGCCCCTGCGCGGAGAAGTC TCCCGAGCAG CGCGGACGCT TCCGCGCCAT 3850 GGTGGAGCTC GCCAGGCTGGATCGGAGGCG GCCGGGGAGC AGCGACAGGG 3900 TCCTCTTCGC GCGGTTCTCG AAGACCGAGGGCGGAGCGAG GCGGGCTTCT 3950 CCAGACCAAG AAGCTGAGGA CCTGTGGCTG AGCCCGCTGACCATGGAAGA 4000 TCTTGTCTGC TACAGCTTCC AGGTGGCCAG AGGGATGGAG TTCCTGGCTT4050 CCCGAAAGTG CATCCACAGA GACCTGGCTG CTCGGAACAT TCTGCTGTCG 4100GAAAGCGACG TGGTGAAGAT CTGTGACTTT GGCCTTGCCC GGGACATCTA 4150 CAAAGACCCTGACTACGTCC GCAAGGGCAG TGCCCGGCTG CCCCTGAAGT 4200 GGATGGCCCC TGAAAGCATCTTCGACAAGG TGTACACCAC GCAGAGTGAC 4250 GTGTGGTCCT TTGGGGTGCT TCTCTGGGAGATCTTCTCTC TGGGGGCCTC 4300 CCCGTACCCT GGGGTGCAGA TCAATGAGGA GTTCTGCCAGCGGCTGAGAG 4350 ACGGCACAAG GATGAGGGCC CCGGAGCTGG CCACTCCCGC CATACGCCGC4400 ATCATGCTGA ACTGCTGGTC CGGAGACCCC AAGGCGAGAC CTGCATTCTC 4450GGAGCTGGTG GAGATCCTGG GGGACCTGCT CCAGGGCAGG GGCCTGCAAG 4500 AGGAAGAGGAGGTCTGCATG GCCCCGCGCA GCTCTCAGAG CTCAGAAGAG 4550 GGCAGCTTCT CGCAGGTGTCCACCATGGCC CTACACATCG CCCAGGCTGA 4600 CGCTGAGGAC AGCCCGCCAA GCCTGCAGCGCCACAGCCTG GCCGCCAGGT 4650 ATTACAACTG GGTGTCCTTT CCCGGGTGCC TGGCCAGAGGGGCTGAGACC 4700 CGTGGTTCCT CCAGGATGAA GACATTTGAG GAATTCCCCA TGACCCCAAC4750 GACCTACAAA GGCTCTGTGG ACAACCAGAC AGACAGTGGG ATGGTGCTGG 4800CCTCGGAGGA GTTTGAGCAG ATAGAGAGCA GGCATAGACA AGAAAGCGGC 4850 TTCAGGTAGCTGAAGCAGAG AGAGAGAAGG CAGCATACGT CAGCATTTTC 4900 TTCTCTGCAC TTATAAGAAAGATCAAAGAC TTTAAGACTT TCGCTATTTC 4950 TTCTGCTATC TACTACAAAC TTCAAAGAGGAACCAGGAGG CCAAGAGGAG 5000 CATGAAAGTG GACAAGGAGT GTGACCACTG AAGCACCACAGGGAGGGGTT 5050 AGGCCTCCGG ATGACTGCGG GCAGGCCTGG ATAATATCCA GCCTCCCACA5100 AGAAGCTGGT GGAGCAGAGT GTTCCCTGAC TCCTCCAAGG AAAGGGAGAC 5150GCCCTTTCAT GGTCTGCTGA GTAACAGGTG CCTTCCCAGA CACTGGCGTT 5200 ACTGCTTGACCAAAGAGCCC TCAAGCGGCC CTTATGCCAG CGTGACAGAG 5250 GGCTCACCTC TTGCCTTCTAGGTCACTTCT CACAATGTCC CTTCAGCACC 5300 TGACCCTGTG CCCGCCAGTT ATTCCTTGGTAATATGAGTA ATACATCAAA 5350 GAGTAGTGCG GCCGCGAATT CCCCGGGGAT CCTCTAGAGTCGACCTGCAG 5400 AAGCTTGGCC GCCATGGCCC AACTTGTTTA TTGCAGCTTA TAATGGTTAC5450 AAATAAAGCA ATAGCATCAC AAATTTCACA AATAAAGCAT TTTTTTCACT 5500GCATTCTAGT TGTGGTTTGT CCAAACTCAT CAATGTATCT TATCATGTCT 5550 GGATCGGGAATTAATTCGGC GCAGCACCAT GGCCTGAAAT AACCTCTGAA 5600 AGAGGAACTT GGTTAGGTACCTTCTGAGGC GGAAAGAACC AGCTGTGGAA 5650 TGTGTGTCAG TTAGGGTGTG GAAAGTCCCCAGGCTCCCCA GCAGGCAGAA 5700 GTATGCAAAG CATGCATCTC AATTAGTCAG CAACCAGGTGTGGAAAGTCC 5750 CCAGGCTCCC CAGCAGGCAG AAGTATGCAA AGCATGCATC TCAATTAGTC5800 AGCAACCATA GTCCCGCCCC TAACTCCGCC CATCCCGCCC CTAACTCCGC 5850CCAGTTCCGC CCATTCTCCG CCCCATGGCT GACTAATTTT TTTTATTTAT 5900 GCAGAGGCCGAGGCCGCCTC GGCCTCTGAG CTATTCCAGA AGTAGTGAGG 5950 AGGCTTTTTT GGAGGCCTAGGCTTTTGCAA AAAGCTGTTA ACAGCTTGGC 6000 ACTGGCCGTC GTTTTACAAC GTCGTGACTGGGAAAACCCT GGCGTTACCC 6050 AACTTAATCG CCTTGCAGCA CATCCCCCTT TCGCCAGCTGGCGTAATAGC 6100 GAAGAGGCCC GCACCGATCG CCCTTCCCAA CAGTTGCGCA GCCTGAATGG6150 CGAATGGCGC CTGATGCGGT ATTTTCTCCT TACGCATCTG TGCGGTATTT 6200CACACCGCAT ACGTCAAAGC AACCATAGTA CGCGCCCTGT AGCGGCGCAT 6250 TAAGCGCGGCGGGTGTGGTG GTTACGCGCA GCGTGACCGC TACACTTGCC 6300 AGCGCCCTAG CGCCCGCTCCTTTCGCTTTC TTCCCTTCCT TTCTCGCCAC 6350 GTTCGCCGGC TTTCCCCGTC AAGCTCTAAATCGGGGGCTC CCTTTAGGGT 6400 TCCGATTTAG TGCTTTACGG CACCTCGACC CCAAAAAACTTGATTTGGGT 6450 GATGGTTCAC GTAGTGGGCC ATCGCCCTGA TAGACGGTTT TTCGCCCTTT6500 GACGTTGGAG TCCACGTTCT TTAATAGTGG ACTCTTGTTC CAAACTGGAA 6550CAACACTCAA CCCTATCTCG GGCTATTCTT TTGATTTATA AGGGATTTTG 6600 CCGATTTCGGCCTATTGGTT AAAAAATGAG CTGATTTAAC AAAAATTTAA 6650 CGCGAATTTT AACAAAATATTAACGTTTAC AATTTTATGG TGCACTCTCA 6700 GTACAATCTG CTCTGATGCC GCATAGTTAAGCCAGCCCCG ACACCCGCCA 6750 ACACCCGCTG ACGCGCCCTG ACGGGCTTGT CTGCTCCCGGCATCCGCTTA 6800 CAGACAAGCT GTGACCGTCT CCGGGAGCTG CATGTGTCAG AGGTTTTCAC6850 CGTCATCACC GAAACGCGCG AGACGAAAGG GCCTCGTGAT ACGCCTATTT 6900TTATAGGTTA ATGTCATGAT AATAATGGTT TCTTAGACGT CAGGTGGCAC 6950 TTTTCGGGGAAATGTGCGCG GAACCCCTAT TTGTTTATTT TTCTAAATAC 7000 ATTCAAATAT GTATCCGCTCATGAGACAAT AACCCTGATA AATGCTTCAA 7050 TAATATTGAA AAAGGAAGAG TATGAGTATTCAACATTTCC GTGTCGCCCT 7100 TATTCCCTTT TTTGCGGCAT TTTGCCTTCC TGTTTTTGCTCACCCAGAAA 7150 CGCTGGTGAA AGTAAAAGAT GCTGAAGATC AGTTGGGTGC ACGAGTGGGT7200 TACATCGAAC TGGATCTCAA CAGCGGTAAG ATCCTTGAGA GTTTTCGCCC 7250CGAAGAACGT TTTCCAATGA TGAGCACTTT TAAAGTTCTG CTATGTGGCG 7300 CGGTATTATCCCGTATTGAC GCCGGGCAAG AGCAACTCGG TCGCCGCATA 7350 CACTATTCTC AGAATGACTTGGTTGAGTAC TCACCAGTCA CAGAAAAGCA 7400 TCTTACGGAT GGCATGACAG TAAGAGAATTATGCAGTGCT GCCATAACCA 7450 TGAGTGATAA CACTGCGGCC AACTTACTTC TGACAACGATCGGAGGACCG 7500 AAGGAGCTAA CCGCTTTTTT GCACAACATG GGGGATCATG TAACTCGCCT7550 TGATCGTTGG GAACCGGAGC TGAATGAAGC CATACCAAAC GACGAGCGTG 7600ACACCACGAT GCCTGTAGCA ATGGCAACAA CGTTGCGCAA ACTATTAACT 7650 GGCGAACTACTTACTCTAGC TTCCCGGCAA CAATTAATAG ACTGGATGGA 7700 GGCGGATAAA GTTGCAGGACCACTTCTGCG CTCGGCCCTT CCGGCTGGCT 7750 GGTTTATTGC TGATAAATCT GGAGCCGGTGAGCGTGGGTC TCGCGGTATC 7800 ATTGCAGCAC TGGGGCCAGA TGGTAAGCCC TCCCGTATCGTAGTTATCTA 7850 CACGACGGGG AGTCAGGCAA CTATGGATGA ACGAAATAGA CAGATCGCTG7900 AGATAGGTGC CTCACTGATT AAGCATTGGT AACTGTCAGA CCAAGTTTAC 7950TCATATATAC TTTAGATTGA TTTAAAACTT CATTTTTAAT TTAAAAGGAT 8000 CTAGGTGAAGATCCTTTTTG ATAATCTCAT GACCAAAATC CCTTAACGTG 8050 AGTTTTCGTT CCACTGAGCGTCAGACCCCG TAGAAAAGAT CAAAGGATCT 8100 TCTTGAGATC CTTTTTTTCT GCGCGTAATCTGCTGCTTGC AAACAAAAAA 8150 ACCACCGCTA CCAGCGGTGG TTTGTTTGCC GGATCAAGAGCTACCAACTC 8200 TTTTTCCGAA GGTAACTGGC TTCAGCAGAG CGCAGATACC AAATACTGTT8250 CTTCTAGTGT AGCCGTAGTT AGGCCACCAC TTCAAGAACT CTGTAGCACC 8300GCCTACATAC CTCGCTCTGC TAATCCTGTT ACCAGTGGCT GCTGCCAGTG 8350 GCGATAAGTCGTGTCTTACC GGGTTGGACT CAAGACGATA GTTACCGGAT 8400 AAGGCGCAGC GGTCGGGCTGAACGGGGGGT TCGTGCACAC AGCCCAGCTT 8450 GGAGCGAACG ACCTACACCG AACTGAGATACCTACAGCGT GAGCTATGAG 8500 AAAGCGCCAC GCTTCCCGAA GGGAGAAAGG CGGACAGGTATCCGGTAAGC 8550 GGCAGGGTCG GAACAGGAGA GCGCACGAGG GAGCTTCCAG GGGGAAACGC8600 CTGGTATCTT TATAGTCCTG TCGGGTTTCG CCACCTCTGA CTTGAGCGTC 8650GATTTTTGTG ATGCTCGTCA GGGGGGCGGA GCCTATGGAA AAACGCCAGC 8700 AACGCGGCCTTTTTACGGTT CCTGGCCTTT TGCTGGCCTT TTGCTCACAT 8750 GTTCTTTCCT GCGTTATCCCCTGATTCTGT GGATAACCGT ATTACCGCCT 8800 TTGAGTGAGC TGATACCGCT CGCCGCAGCCGAACGACCGA GCGCAGCGAG 8850 TCAGTGAGCG AGGAAGCGGA AGAGCGCCCA ATACGCAAACCGCCTCTCCC 8900 CGCGCGTTGG CCGATTCATT AATGCAGCTG GCACGACAGG TTTCCCGACT8950 GGAAAGCGGG CAGTGAGCGC AACGCAATTA ATGTGAGTTA GCTCACTCAT 9000TAGGCACCCC AGGCTTTACA CTTTATGCTT CCGGCTCGTA TGTTGTGTGG 9050 AATTGTGAGCGGATAACAAT TTCACACAGG AAACAGCTAT GACATGATTA 9100 CGAATTAA 9108

The invention claimed is:
 1. A method for activating the kinase domainof SAL-S1 receptor protein tyrosine kinase comprising contacting theextracellular domain of the SAL-S1 receptor protein tyrosine kinase withan effective amount of an agonist antibody thereto such that thetyrosine kinase domain of the SAL-S1 receptor protein tyrosine kinase isactivated.
 2. The method of claim 1, wherein said agonist antibody is amonoclonal antibody.
 3. The method of claim 1, wherein said agonistantibody comprises non-human CDR residues and human immunoglobulinresidues.
 4. The method of claim 1, wherein said agonist antibody isadmixed with a pharmaceutially acceptable carrier.
 5. The method ofclaim 1, wherein activation of said tyrosine kinase domain induces cellgrowth and/or differentiation.
 6. The method of claim 5, wherein saidinduced cell growth and/or differentation occurs in a megakaryocyte.